Methods for generating and delivering droplets to the pulmonary system using a droplet delivery device

ABSTRACT

A droplet delivery device and related methods for delivering precise and repeatable dosages to a subject for pulmonary use is disclosed. The droplet delivery device includes a housing, a reservoir, and ejector mechanism, and at least one differential pressure sensor. The droplet delivery device is automatically breath actuated by the user when the differential pressure sensor senses a predetermined pressure change within housing. The droplet delivery device is then actuated to generate a stream of droplets having an average ejected droplet diameter within the respirable size range, e.g, less than about 5 μm, so as to target the pulmonary system of the user.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of PCT Application No.PCT/US2017/030917, entitled “METHODS FOR GENERATING AND DELIVERINGDROPLETS TO THE PULMONARY SYSTEM USING A DROPLET DELIVERY DEVICE,” filedon May 3, 2017, which claims benefit under 35 U.S.C. §119 of: U.S.Provisional Patent Application No. 62/331,328, entitled “DISPOSABLEPULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE,” filed on May 3,2016; U.S. Provisional Patent Application No. 62/332,352, entitled“DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE,” filedon May 5, 2016; U.S. Provisional Patent Application No. 62/334,076,entitled “DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OFUSE,” filed on May 10, 2016; U.S. Provisional Patent Application No.62/354,437, entitled “DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS ANDMETHODS OF USE,” filed on Jun. 24, 2016; U.S. Provisional PatentApplication No. 62/399,091, entitled “DISPOSABLE PULMONARY DRUG DELIVERYAPPARATUS AND METHODS OF USE,” filed on Sep. 23, 2016; U.S. ProvisionalPatent Application No. 62/416,026, entitled “DISPOSABLE PULMONARY DRUGDELIVERY APPARATUS AND METHODS OF USE,” filed on Nov. 1, 2016; U.S.Provisional Patent Application No. 62/422,932, entitled “DISPOSABLEPULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE,” filed on Nov. 16,2016; U.S. Provisional Patent Application No. 62/428,696, entitled“DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OF USE,” filedon Dec. 1, 2016; U.S. Provisional Patent Application No. 62/448,796,entitled “DISPOSABLE PULMONARY DRUG DELIVERY APPARATUS AND METHODS OFUSE,” filed on Jan. 20, 2017; and U.S. Provisional Patent ApplicationNo. 62/471,929, entitled “DISPOSABLE PULMONARY DRUG DELIVERY APPARATUSAND METHODS OF USE,” filed on Mar. 15, 2017. The content of eachapplication is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This disclosure relates to droplet delivery devices and morespecifically to droplet delivery devices for the delivery of fluids tothe pulmonary system.

BACKGROUND OF THE INVENTION

The use of aerosol generating devices for the treatment of a variety ofrespiratory diseases is an area of large interest. Inhalation providesfor the delivery of aerosolized drugs to treat asthma, COPD andsite-specific conditions, with reduced systemic adverse effects. A majorchallenge is providing a device that delivers an accurate, consistent,and verifiable dose, with a droplet size that is suitable for successfuldelivery of medication to the targeted lung passageways.

Dose verification, delivery and inhalation of the correct dose atprescribed times is important. Getting patients to use inhalerscorrectly is also a major problem. A need exists to insure that patientscorrectly use inhalers and that they administer the proper dose atprescribed times. Problems emerge when patients misuse or incorrectlyadminister a dose of their medication. Unexpected consequences occurwhen the patient stops taking medications, owing to not feeling anybenefit, or when not seeing expected benefits or overuse the medicationand increase the risk of over dosage. Physicians also face the problemof how to interpret and diagnose the prescribed treatment when thetherapeutic result is not obtained.

Currently most inhaler systems such as metered dose inhalers (MDI) andpressurized metered dose inhalers (p-MDI) or pneumatic andultrasonic-driven devices generally produce drops with high velocitiesand a wide range of droplet sizes including large droplet that have highmomentum and kinetic energy. Droplets and aerosols with such highmomentum do not reach the distal lung or lower pulmonary passageways butare deposited in the mouth and throat. As a result, larger total drugdoses are required to achieve the desired deposition in targeted areas.These large doses increase the probability of unwanted side effects.

Aerosol plumes generated from current aerosol delivery systems, as aresult of their high ejection velocities and the rapid expansion of thedrug carrying propellant, may lead to localized cooling and subsequentcondensation, deposition and crystallization of drug onto the ejectorsurfaces. Blockage of ejector apertures by deposited drug residue isalso problematic.

This phenomenon of surface condensation is also a challenge for existingvibrating mesh or aperture plate nebulizers that are available on themarket. In these systems, in order to prevent a buildup of drug ontomesh aperture surfaces, manufacturers require repeated washing andcleaning, as well as disinfection after a single use in order to preventpossible microbiological contamination. Other challenges includedelivery of viscous drugs and suspensions that can clog the apertures orpores and lead to inefficiency or inaccurate drug delivery to patientsor render the device inoperable. Also, the use of detergents or othercleaning or sterilizing fluids may damage the ejector mechanism or otherparts of the nebulizer and lead to uncertainty as to the ability of thedevice to deliver a correct dose to the patient or state of performanceof the device.

Accordingly, there is a need for an inhaler device that deliversparticles of a suitable size range, avoids surface fluid deposition andblockage of apertures, with a dose that is verifiable, and providesfeedback regarding correct and consistent usage of the inhaler topatient and professional such as physician, pharmacist or therapist.

SUMMARY OF THE INVENTION

In one aspect, the disclosure relates to a method for generating anddelivering a fluid as an ejected stream of droplets to the pulmonarysystem of a subject in a respirable range. The method may comprise: (a)generating an ejected stream of droplets via a piezoelectric actuateddroplet delivery device, wherein at least about 70% of the ejectedstream of droplets have an average ejected droplet diameter of less thanabout 5 μm; and (b) delivering the ejected stream of droplets to thepulmonary system of the subject such that at least about 70% of the massof the ejected stream of droplets is delivered in a respirable range tothe pulmonary system of a subject during use.

In other aspects, the ejected stream of droplets of the disclosed methodare subjected to an approximate 90 degree change of trajectory withinthe piezoelectric actuated droplet delivery device such that dropletshaving a diameter greater than about 5 μm are filtered from the ejectedstream of droplets due to inertial forces, without being carried inentrained airflow through and out of the piezoelectric actuated dropletdelivery device to the pulmonary system of the subject. In yet otheraspects, the filtering of droplets having a diameter greater than about5 μm increases the mass of the ejected stream of droplets delivered tothe pulmonary system of the subject during use. In other aspects, theejected stream of droplets may further comprise droplets having anaverage ejected droplet diameter of between about 5 μm to about 10 μm.In further aspects, the ejected stream of droplets may comprise atherapeutic agent for the treatment of a pulmonary disease, disorder, orcondition.

In further aspects, the piezoelectric actuated droplet delivery devicemay comprise: a housing; a reservoir disposed within or in fluidcommunication with the housing for receiving a volume of fluid; anejector mechanism in fluid communication with the reservoir, the ejectormechanism comprising a piezoelectric actuator and an aperture plate, theaperture plate having a plurality of openings formed through itsthickness and the piezoelectric actuator operable to oscillate theaperture plate at a frequency to thereby generate an ejected stream ofdroplets; and at least one differential pressure sensor positionedwithin the housing, the at least one differential pressure sensorconfigured to activate the ejector mechanism upon sensing apre-determined pressure change within the housing to thereby generate anejected stream of droplets.

In yet further aspects, the aperture plate of the piezoelectric actuateddroplet delivery device comprises a domed shape. In other aspects, thepiezoelectric actuated droplet delivery device further comprises alaminar flow element located at the airflow entrance side of the housingand configured to facilitate laminar airflow across the exit side ofaperture plate and to provide sufficient airflow to ensure that theejected stream of droplets flows through the droplet delivery deviceduring use.

In another aspect, the disclosure relates to a piezoelectric actuateddroplet delivery device for delivering a fluid as an ejected stream ofdroplets to the pulmonary system of a subject. The droplet deliverydevice may include: a housing; a reservoir disposed within or in fluidcommunication with the housing for receiving a volume of fluid; anejector mechanism in fluid communication with the reservoir, the ejectormechanism comprising a piezoelectric actuator and an aperture plate, theaperture plate having a plurality of openings formed through itsthickness and the piezoelectric actuator operable to oscillate theaperture plate at a frequency to thereby generate an ejected stream ofdroplets, at least one differential pressure sensor positioned withinthe housing; the at least one differential pressure sensor configured toactivate the ejector mechanism upon sensing a pre-determined pressurechange within the housing to thereby generate an ejected stream ofdroplets; the ejector mechanism configured to generate the ejectedstream of droplets wherein at least about 70% of the droplets have anaverage ejected droplet diameter of less than about 5 microns, such thatat least about 70% of the mass of the ejected stream of droplets isdelivered in a respirable range to the pulmonary system of a subjectduring use.

In certain aspects, the droplet delivery device further includes asurface tension plate between the aperture plate and the reservoir,wherein the surface tension plate is configured to increase contactbetween the volume of fluid and the aperture plate. In other aspects,the ejector mechanism and the surface tension plate are configured inparallel orientation. In yet other aspects, the surface tension plate islocated within 2 mm of the aperture plate so as to create sufficienthydrostatic force to provide capillary flow between the surface tensionplate and the aperture plate.

In yet other aspects, the aperture plate of the droplet delivery devicecomprises a domed shape. In other aspects, the aperture plate iscomposed of a material selected from the group consisting of poly etherether ketone (PEEK), polyimide, polyetherimide, polyvinylidine fluoride(PVDF), ultra-high molecular weight polyethylene (UHMWPE), Ni, NiCo, Pd,Pt, NiPd, metal alloys, and combinations thereof. In other aspects, oneor more of the plurality of openings of the aperture plate havedifferent cross-sectional shapes or diameters to thereby provide ejecteddroplets having different average ejected droplet diameters.

In some aspects, the droplet delivery device further includes a laminarflow element located at the airflow entrance side of the housing andconfigured to facilitate laminar airflow across the exit side ofaperture plate and to provide sufficient airflow to ensure that theejected stream of droplets flows through the droplet delivery deviceduring use. In other aspects, the droplet delivery device may furtherinclude a mouthpiece coupled with the housing opposite the laminar flowelement.

In other aspects the ejector mechanism of the droplet delivery device isorientated with reference to the housing such that the ejected stream ofdroplets is directed into and through the housing at an approximate 90degree change of trajectory prior to expulsion from the housing.

In yet other aspects, the reservoir of the droplet delivery device isremovably coupled with the housing. In other aspects, the reservoir ofthe droplet delivery device is coupled to the ejector mechanism to forma combination reservoir/ejector mechanism module, and the combinationreservoir/ejector mechanism module is removably coupled with thehousing.

In other aspects, the droplet delivery device may further include awireless communication module. In some aspects, the wirelesscommunication module is a Bluetooth transmitter.

In yet other aspects, the droplet delivery device may further includeone or more sensors selected from an infer-red transmitter, aphotodetector, an additional pressure sensor, and combinations thereof.

In a further aspect, the disclosure relates to a breath actuated dropletdelivery device for delivering a fluid as an ejected stream of dropletsto the pulmonary system of a subject. The device may include: a housing;a combination reservoir/ejector mechanism module in fluid communicationwith the housing for receiving a volume of fluid and generating anejected stream of droplets; the ejector mechanism comprising apiezoelectric actuator and an aperture plate comprising a domed shape,the aperture plate having a plurality of openings formed through itsthickness and the piezoelectric actuator operable to oscillate theaperture plate at a frequency to thereby generate the ejected stream ofdroplets; at least one differential pressure sensor positioned withinthe housing; the at least one differential pressure sensor configured toactivate the ejector mechanism to generate the ejected stream ofdroplets upon sensing a pre-determined pressure change within thehousing when a subject applies an inspiratory breath to an airflow exitside of the housing; the ejector mechanism configured to generate theejected stream of droplets wherein at least about 70% of the dropletshave an average ejected droplet diameter of less than about 5 microns,such that at least about 70% of the mass of the ejected stream ofdroplets is delivered in a respirable range to the pulmonary system ofthe subject during use.

In other aspects, the domed-shape aperture plate of the breath actuateddroplet delivery device is composed of a material selected from thegroup consisting of poly ether ether ketone (PEEK), polyimide,polyetherimide, polyvinylidine fluoride (PVDF), ultra-high molecularweight polyethylene (UHMWPE), Ni, NiCo, Pd, Pt, NiPd, metal alloys, andcombinations thereof.

In other aspects, the breath actuated droplet delivery device furtherincludes a laminar flow element located at an airflow entrance side ofthe housing and configured to facilitate laminar airflow across the exitside of aperture plate and to provide sufficient airflow to ensure thatthe ejected stream of droplets flows through the droplet delivery deviceduring use. In yet other aspects, the breath actuated droplet deliverydevice further includes a mouthpiece coupled with the housing oppositethe laminar flow element.

In a further aspect, this disclosure relates to a method of filteringlarge droplets from an aerosolized plume using inertial forces. Themethod may include: generating an ejected stream of droplets using adroplet delivery device, wherein the ejector mechanism is orientatedwith reference to the housing such that the ejected stream of dropletsis directed into and through the housing at an approximate 90 degreechange of trajectory prior to expulsion from the housing; and whereindroplets having an diameter greater than about 5 μm are deposited on thesidewalls of the housing due to inertial forces, without being carriedin entrained airflow through and out of the droplet delivery device tothe pulmonary system of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more clearly understood from the followingdescription given by way of example, in which:

FIG. 1A is a diagram displaying automatic breath actuation and inertialfiltering using a droplet delivery device in accordance with anembodiment of the disclosure.

FIGS. 1B-1E-3 illustrates an example of an inhalation detection systemthat senses airflow by detecting pressure differentials across flowrestriction. Referring to FIG. 1B and FIG. 1C, illustrate exemplarylocation of the pressure sensors and restrictions. FIG. 1B is an examplewhere the restriction is internal to the mouthpiece tube. FIG. 1C, is anexample where the restriction is located at the laminar flow element andthe pressure is sensed as the differential between the interior of themouthpiece tube and the pressure outside the tube. FIG. 1D is a screencapture of the delta P sensor response to an inhaled breath of a ˜1second duration. FIG. 1E-1, FIG. 1E-2, and FIG. 1E-3 depict the delta Psensor design and its assembly onto a device board (FIG. 1E-1). Thesensor has pneumatic connection through the hole in the printed circuitboard (PCB) and may be mounted either on the main PCB as shown onschemes (FIG. 1E-2) or on a daughter board on scheme (FIG. 1E-3).

FIG. 2A is a cross sectional view of a droplet delivery device inaccordance with an embodiment of the disclosure. FIG. 2B is anenlargement of an ejector mechanism in accordance with an embodiment ofFIG. 2A.

FIG. 2C is an exploded view of the droplet delivery device.

FIG. 2D is a topview of a mouthpiece tube, in accordance with anembodiment of the disclosure.

FIG. 2E is a frontview of a mouthpiece tube with an air aperture grid oropening, in accordance with an embodiment of the disclosure.

FIG. 3A is another embodiment of a droplet delivery device, FIG. 3B isan enlarged view of an ejector mechanism of the device of FIG. 3A, andFIG. 3C is an enlargement of a surface tension plate of the device ofFIG. 3A, in accordance with an embodiment of the disclosure.

FIGS. 4A-4B illustrate an embodiment of a combination reservoir/ejectormechanism module. FIG. 4A-1 shows an exploded view, FIG. 4A-2 shows atop view, FIG. 4A-3 shows a cross sectional view, and FIG. 4A-4 shows anenlarged view of a portion of a module and mechanism for mechanicalmounting of the ejector mechanism to the reservoir, in accordance withan embodiment of the disclosure. FIG. 4B shows a side view of anexemplary superhydrophobic filter and micron-sized aperture forrestricting evaporation, in accordance with an embodiment of thedisclosure.

FIGS. 5A-5G provide an exemplary ejector closure mechanism, inaccordance with an embodiment of the disclosure. FIG. 5A illustrates theejector closure mechanism in an open position, and FIG. 5B illustratesthe ejector closure mechanism in a closed position. FIG. 5C-5Eillustrate detailed views of an exemplary ejector closure mechanism inaccordance with an embodiment of the disclosure, including a top coverin FIG. 5C, and a motor in stages of actuation in FIGS. 5D-5E. FIGS.5F-5G provide an exploded view of an exemplary ejector closure mechanismin accordance with an embodiment of the disclosure.

FIG. 6A is a plot of the differential pressure as a function of flowrates through the laminar flow elements mounted on droplet deliverydevice of the disclosure, as a function of number of holes.

FIG. 6B is a plot of the differential pressure as a function of flowrates through the laminar flow element as a function of screen hole sizeand number of holes set at a constant, 17 holes.

FIG. 6C is a diagram of an air inlet laminar flow screen with 29 holes,each 1.9 mm in diameter.

FIGS. 7A-7B depict exemplary ejector mechanism designs, in accordancewith embodiments of the disclosure.

FIGS. 8A-8B depict perspective and side views of an exemplarydomed-shaped aperture plate design, in accordance with embodiments ofthe disclosure.

FIG. 9 depicts an aperture plate opening design, in accordance withembodiments of the disclosure.

FIGS. 10A-10B are frequency sweep plots displaying medium dampinginfluence on resonant frequency for planar (FIG. 10A) and dome-shapedaperture plates (FIG. 10B), in accordance with embodiments of thedisclosure.

FIG. 11, including insets FIGS. 11-1-11-3 illustrate a graph of aDHM-based frequency sweep versus amplitude of displacement of adomed-shaped aperture plate from 50 kHz to 150 kHz and excitationvoltage; 5 Vpp. Enlarged in insets at FIGS. 11-1-FIGS. 11-3 are Eigenmode shapes associated with resonance frequencies 59 kHz (FIG. 11-1),105 kHz (FIGS. 11-2), and 134 kHz (FIG. 11-3).

FIGS. 12A-12B illustrate the relationship between aperture plate domeheight and active area diameter, in accordance with embodiments of thedisclosure. In FIG. 12A, d is the active area diameter and h is theaperture plate dome height. FIG. 12B shows a plot of the calculation ofdome height, and aperture plate height versus active area.

FIG. 13 is an exploded view of reservoir including a flexible drugampule, in accordance with an embodiment of the disclosure.

FIGS. 14A-14B are top views of exemplary surface tension plates, inaccordance with embodiments of the disclosure.

FIG. 15A shows an exemplary top view of a surface tension plate inaccordance with an embodiment of the disclosure.

FIG. 15B illustrates the effect of surface tension plate distance fromaperture plate and surface tension plate composition on mass deposition,(averages of five, 2.2 sec actuations).

FIG. 16A illustrates a cross-section of a dual combinationreservoir/ejector mechanism module, in accordance with an embodiment ofthe disclosure.

FIG. 16B illustrates a droplet delivery device with a dual combinationreservoir/ejector mechanism module, in accordance with an embodiment ofthe disclosure.

FIG. 17A is a negative image recorded for droplet generation by dropletdelivery device, in accordance with an embodiment of the disclosure.

FIG. 17B illustrates a view of inertial filtering for filtering andexcluding larger droplets from the aerosol plume, showing droplet flowfrom a droplet delivery device of the disclosure, with region 1representing a region of laminar flow and region 2 representing a regionof turbulent flow due to the generation of entrained air. Dropletsundergo a 90 degree change in spray direction (4-5) as droplets emergefrom the ejector mechanism and are swept by the airflow (3) through thelaminar flow elements before inhalation into the pulmonary airways.

FIGS. 17C-17D depict inertial filter with a mechanism to select dropletsize distribution by varying droplet exit angle.

FIGS. 18A-18B are examples of spray verification using (FIG. 18A) deepred LED (650 nm) and/or (FIG. 18B) near IR LED (850 nm) laser andphotodiode detectors.

FIG. 19 illustrates a system comprising a droplet delivery device incombination with a mechanical ventilator, in accordance with certainembodiments of the disclosure.

FIG. 20 illustrates a system comprising a droplet delivery device incombination with a CPAP machine, e.g., to assist with cardiac eventsduring sleep, in accordance with certain embodiments of the disclosure.

FIG. 21A provides a summary of the mass fraction collected duringAnderson Cascade Impactor testing a droplet delivery device ofdisclosure.

FIG. 21B is a summary of MMAD and GSD droplet data obtained duringAnderson Cascade impactor testing of a droplet delivery device of thedisclosure (3 cartridges, 10 actuations per cartridge; Albuterol, 0.5%,28.3 lpm; 30 actuations total).

FIG. 21C-1 and FIG. 21C-2 are cumulative plots of the aerodynamic sizedistribution of data displayed in FIG. 21A.

FIG. 21D is a summary of Throat, Coarse, Respirable and Fine ParticleFraction. Anderson Cascade Impact testing a droplet delivery device ofdisclosure (3 cartridges 10 actuations per cartridge; Albuterol, 0.5%,28.3 lpm; 30 actuations total).

FIGS. 22A-22B are comparison of aerosol plumes from a droplet deliverydevice of the disclosure (FIG. 22A) and Respimat Soft Mist Inhale (FIG.22B).

FIG. 23A is a comparison of MMAD and GSD data for a droplet deliverydevice of the disclosure, Respimat, and ProAir Inhaler Devices (AndersonCascade Impactor Testing, 28.3 lpm, Mean+/−SD, 3 devices, 10 actuationsper device).

FIG. 23B is a summary of Coarse, Respirable and Fine Fractions for adroplet delivery device of the disclosure, Respimat, and ProAir InhalerDevices (Anderson Cascade Impactor Testing, 28.3 lpm, Mean+/−SD, 3devices, 10 actuations per device).

FIGS. 24A-24B, show SEC chromatographs of control (FIG. 24A) andaerosolized Enbrel solutions (FIG. 24B) produced using a dropletdelivery device of the disclosure.

FIGS. 25A-25B, show SEC chromatographs of control (FIG. 25A) andaerosolized Insulin solutions (FIG. 25B) produced using a dropletdelivery device of the disclosure.

DETAILED DESCRIPTION

Effective delivery of medication to the deep pulmonary regions of thelungs through the alveoli, has always posed a problem, especially tochildren and elderly, as well as to those with the diseased state, owingto their limited lung capacity and constriction of the breathingpassageways. The impact of constricted lung passageways limits deepinspiration and synchronization of the administered dose with theinspiration/expiration cycle. For optimum deposition in alveolarairways, particles with aerodynamic diameters in the ranges of 1 to 5 μmare optimal, with particles below about 4 μm shown to reach the alveolarregion of the lungs, while larger particles are deposited on the tongueor strike the throat and coat the bronchial passages. Smaller particles,for example less than about 1 μm that penetrate more deeply into thelungs have a tendency to be exhaled.

In certain aspects, the present disclosure relates to a droplet deliverydevice for delivery a fluid as an ejected stream of droplets to thepulmonary system of a subject and related methods of delivering safe,suitable, and repeatable dosages to the pulmonary system of a subject.The present disclosure also includes a droplet delivery device andsystem capable of delivering a defined volume of fluid in the form of anejected stream of droplets such that an adequate and repeatable highpercentage of the droplets are delivered into the desired locationwithin the airways, e.g., the alveolar airways of the subject duringuse.

The present disclosure provides a droplet delivery device for deliveryof a fluid as an ejected stream of droplets to the pulmonary system of asubject, the device comprising a housing, a reservoir for receiving avolume of fluid, and an ejector mechanism including a piezoelectricactuator and an aperture plate, wherein the ejector mechanism isconfigured to eject a stream of droplets having an average ejecteddroplet diameter of less than 5 microns. In specific embodiments, theejector mechanism is activated by at least one differential pressuresensor located within the housing of the droplet delivery device uponsensing a pre-determined pressure change within the housing. In certainembodiments, such a pre-determined pressure change may be sensed duringan inspiration cycle by a user of the device, as will be explained infurther detail herein.

In accordance with certain aspects of the disclosure, effectivedeposition into the lungs generally requires droplets less than 5 μm indiameter. Without intending to be limited by theory, to deliver fluid tothe lungs a droplet delivery device must impart a momentum that issufficiently high to permit ejection out of the device, but sufficientlylow to prevent deposition on the tongue or in the back of the throat.Droplets below 5 μm in diameter are transported almost completely bymotion of the airstream and entrained air that carry them and not bytheir own momentum.

In certain aspects, the present disclosure includes and provides anejector mechanism configured to eject a stream of droplets within therespirable range of less than 5 μm. The ejector mechanism is comprisedof an aperture plate that is directly or indirectly coupled to apiezoelectric actuator. In certain implementations, the aperture platemay be coupled to an actuator plate that is coupled to the piezoelectricactuator. The aperture plate generally includes a plurality of openingsformed through its thickness and the piezoelectric actuator directly orindirectly (e.g. via an actuator plate) oscillates the aperture plate,having fluid in contact with one surface of the aperture plate, at afrequency and voltage to generate a directed aerosol stream of dropletsthrough the openings of the aperture plate into the lungs, as thepatient inhales. In other implementations where the aperture plate iscoupled to the actuator plate, the actuator plate is oscillated by thepiezoelectric oscillator at a frequency and voltage to generate adirected aerosol stream or plume of aerosol droplets.

In certain aspects, the present disclosure relates to a droplet deliverydevice for delivering a fluid as an ejected stream of droplets to thepulmonary system of a subject. In certain aspects, the therapeuticagents may be delivered at a high dose concentration and efficacy, ascompared to alternative dosing routes and standard inhalationtechnologies.

In certain embodiments, the droplet delivery devices of the disclosuremay be used to treat various diseases, disorders and conditions bydelivering therapeutic agents to the pulmonary system of a subject. Inthis regard, the droplet delivery devices may be used to delivertherapeutic agents both locally to the pulmonary system, andsystemically to the body.

More specifically, the droplet delivery device may be used to delivertherapeutic agents as an ejected stream of droplets to the pulmonarysystem of a subject for the treatment or prevention of pulmonarydiseases or disorders such as asthma, chronic obstructive pulmonarydiseases (COPD) cystic fibrosis (CF), tuberculosis, chronic bronchitis,or pneumonia. In certain embodiments, the droplet delivery device may beused to deliver therapeutic agents such as COPD medications, asthmamedications, or antibiotics. By way of non-limiting example, suchtherapeutic agents include albuterol sulfate, ipratropium bromide,tobramycin, and combinations thereof.

In other embodiments, the droplet delivery device may be used for thesystemic delivery of therapeutic agents including small molecules,therapeutic peptides, proteins, antibodies, and other bioengineeredmolecules via the pulmonary system. By way of non-limiting example, thedroplet delivery device may be used to systemically deliver therapeuticagents for the treatment or prevention of indications inducing, e.g.,diabetes mellitus, rheumatoid arthritis, plaque psoriasis, Crohn'sdisease, hormone replacement, neutropenia, nausea, influenza, etc.

By way of non-limiting example, therapeutic peptides, proteins,antibodies, and other bioengineered molecules include: growth factors,insulin, vaccines (Prevnor-Pneumonia, Gardasil-HPV), antibodies(Avastin, Humira, Remicade, Herceptin), Fc Fusion Proteins (Enbrel,Orencia), hormones (Elonva-long acting FSH, Growth Hormone), enzymes(Pulmozyme-rHu-DNAase-), other proteins (Clotting factors, Interleukins,Albumin), gene therapy and RNAi, cell therapy (Provenge-Prostate cancervaccine), antibody drug conjugates-Adcetris (Brentuximab vedotin forHL), cytokines, anti-infective agents, polynucleotides, oligonucleotides(e.g., gene vectors), or any combination thereof; or solid particles orsuspensions such as Flonase (fluticasone propionate) or Advair(fluticasone propionate and salmeterol xinafoate).

In other embodiments, the droplet delivery device of the disclosure maybe used to deliver a solution of nicotine including the water-nicotineazeotrope for the delivery of highly controlled dosages for smokingcessation or a condition requiring medical or veterinary treatment. Inaddition, the fluid may contain THC, CBD, or other chemicals containedin marijuana for the treatment of seizures and other conditions.

In certain embodiments, the drug delivery device of the disclosure maybe used to deliver scheduled and controlled substances such as narcoticsfor the highly controlled dispense of pain medications where dosing isonly enabled by doctor or pharmacy communication to the device, andwhere dosing may only be enabled in a specific location such as thepatient's residence as verified by GPS location on the patient's smartphone. This mechanism of highly controlled dispensing of controlledmedications can prevent the abuse or overdose of narcotics or otheraddictive drugs.

Certain benefits of the pulmonary route for delivery of drugs and othermedications include a non-invasive, needle-free delivery system that issuitable for delivery of a wide range of substances from small moleculesto very large proteins, reduced level of metabolizing enzymes comparedto the GI tract and absorbed molecules do not undergo a first passeffect. (A. Tronde, et al., J Pharm Sci, 92 (2003) 1216-1233; A. L.Adjei, et al., Inhalation Delivery of Therapeutic Peptides and Proteins,M. Dekker, New York, 1997). Further, medications that are administeredorally or intravenously are diluted through the body, while medicationsgiven directly into the lungs may provide concentrations at the targetsite (the lungs) that are about 100 times higher than the sameintravenous dose. This is especially important for treatment of drugresistant bacteria, drug resistant tuberculosis, for example and toaddress drug resistant bacterial infections that are an increasingproblem in the ICU.

Another benefit for giving medication directly into the lungs is thathigh, toxic levels of medications in the blood stream their associatedside effects can be minimized. For example intravenous administration oftobramycin leads to very high serum levels that are toxic to the kidneysand therefore limits its use, while administration by inhalationsignificantly improves pulmonary function without severe side effects tokidney functions. (Ramsey et al., Intermittent administration of inhaledtobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23-30; MacLusky et al., Long-term effects of inhaled tobramycin inpatients with cystic fibrosis colonized with Pseudomonas aeruginosa.Pediatr Pulmonol 1989; 7:42-48; Geller et al., Pharmacokinetics andbioavailablility of aerosolized tobramycin in cystic fibrosis. Chest2002; 122:219-226.)

As discussed above, effective delivery of droplets deep into the lungairways require droplets that are less than 5 microns in diameter,specifically droplets with mass mean aerodynamic diameters (MMAD) thatare less than 5 microns. The mass mean aerodynamic diameter is definedas the diameter at which 50% of the particles by mass are larger and 50%are smaller. In certain aspects of the disclosure, in order to depositin the alveolar airways, droplet particles in this size range must havemomentum that is sufficiently high to permit ejection out of the device,but sufficiently low to overcome deposition onto the tongue (softpalate) or pharynx.

In other aspects of the disclosure, methods for generating an ejectedstream of droplets for delivery to the pulmonary system of user usingthe droplet delivery devices of the disclosure are provided. In certainembodiments, the ejected stream of droplets is generated in acontrollable and defined droplet size range. By way of example, thedroplet size range includes at least about 50%, at least about 60%, atleast about 70%, at least about 85%, at least about 90%, between about50% and about 90%, between about 60% and about 90%, between about 70%and about 90%, etc., of the ejected droplets are in the respirable rangeof below about 5 μm.

In other embodiments, the ejected stream of droplets may have one ormore diameters, such that droplets having multiple diameters aregenerated so as to target multiple regions in the airways (mouth,tongue, throat, upper airways, lower airways, deep lung, etc.) By way ofexample, droplet diameters may range from about 1 μm to about 200 μm,about 2 μm to about 100 μm, about 2 μm to about 60 μm, about 2 μm toabout 40 μm, about 2 μm to about 20 μm, about 1 μm to about 5 μm, about1 μm to about 4.7 μm, about 1 μm to about 4 μm, about 10 μm to about 40μm, about 10 μm to about 20 μm, about 5 μm to about 10 μm, andcombinations thereof. In particular embodiments, at least a fraction ofthe droplets have diameters in the respirable range, while otherparticles may have diameters in other sizes so as to targetnon-respirable locations (e.g., larger than 5 μm). Illustrative ejecteddroplet streams in this regard might have 50%-70% of droplets in therespirable range (less than about 5 μm), and 30%-50% outside of therespirable range (about 5-about 10 μm, about 5-about 20 μm, etc.)

In another embodiment, methods for delivering safe, suitable, andrepeatable dosages of a medicament to the pulmonary system using thedroplet delivery devices of the disclosure are provided. The methodsdeliver an ejected stream of droplets to the desired location within thepulmonary system of the subject, including the deep lungs and alveolarairways.

In certain aspects of the disclosure, a droplet delivery device fordelivery an ejected stream of droplets to the pulmonary system of asubject is provided. The droplet delivery device generally includes ahousing and a reservoir disposed in or in fluid communication with thehousing, an ejector mechanism in fluid communication with the reservoir,and at least one differential pressure sensor positioned within thehousing. The differential pressure sensor is configured to activate theejector mechanism upon sensing a pre-determined pressure change withinthe housing, and the ejector mechanism is configured to generate acontrollable plume of an ejected stream of droplets. The ejected streamof droplets includes, without limitation, solutions, suspensions oremulsions which have viscosities in a range capable of droplet formationusing the ejector mechanism. The ejector mechanism may include apiezoelectric actuator which is directly or indirectly coupled to anaperture plate having a plurality of openings formed through itsthickness. The piezoelectric actuator is operable to directly orindirectly oscillate the aperture plate at a frequency to therebygenerate an ejected stream of droplets.

In certain embodiments, the droplet delivery device may include acombination reservoir/ejector mechanism module that may be replaceableor disposable either on a periodic basis, e.g., a daily, weekly,monthly, as-needed, etc. basis, as may be suitable for a prescription orover-the-counter medication. The reservoir may be prefilled and storedin a pharmacy for dispensing to patients or filled at the pharmacy orelsewhere by using a suitable injection means such as a hollow injectionsyringe driven manually or driven by a micro-pump. The syringe may fillthe reservoir by pumping fluid into or out of a rigid container or othercollapsible or non-collapsible reservoir. In certain aspects, suchdisposable/replaceable, combination reservoir/ejector mechanism modulemay minimize and prevent buildup of surface deposits or surfacemicrobial contamination on the aperture plate, owing to its short in-usetime.

The present disclosure also provides a droplet delivery device that isaltitude insensitive. In certain implementations, the droplet deliverydevice is configured so as to be insensitive to pressure differentialsthat may occur when the user travels from sea level to sub-sea levelsand at high altitudes, e.g., while traveling in an airplane wherepressure differentials may be as great as 4 psi. As will be discussed infurther detail herein, in certain implementations of the disclosure, thedroplet delivery device may include a superhydrophobic filter whichprovides for free exchange of air across the filter into and out of thereservoir, while blocking moisture or fluids from passing through thefilter, thereby reducing or preventing fluid leakage or deposition onaperture plate surfaces.

Reference will now be made to the figures, with like componentsillustrates with like references numbers.

Referring to FIG. 1A, in one aspect of the disclosure, a dropletdelivery device 100 is illustrated in use by a patient. Droplet deliverydevice 100 may include one or more differential pressure sensors (notshown) to provide for automatic electronic breath actuation of thedevice. Such pressure sensor(s) automatically detects a desired pointduring a user's inhalation cycle to activate the actuation of ejectormechanism 104 to generate an ejected stream of droplets. For instance, auser may begin to inhale, pulling air through the back of the device at1, triggering the differential pressure sensor and thereby activatingactuation of ejector mechanism 104 to generate an ejected stream ofdroplets at 2, which stream of droplets are entrained in the user'sinhalation airflow thereby traveling along the device and into theuser's airway at 3. As will be explained in further detail herein, anylarge droplets are removed from the entrained airflow via inertialfiltering, falling to the bottom surface of the device at 4. By way ofnon-limiting example, the pressure sensor(s) may be programmed totrigger a 2 second ejection when the user generated airflow within thedevice is about 10 SLM or similar pressure. However, any suitabledifferential pressure within a standard physiological range of a targetuser may be used. Such a trigger point during the inspiratory cycle mayprovide an optimum point during a user's inhalation cycle to activateand actuate the generation of an ejected stream of droplets, anddelivery of medication. Since electronic breath actuation does notrequire user-device coordination, the droplet delivery devices andmethods of the disclosure further provide assurance for optimum deliveryof inhaled medication.

By way of non-limiting example, FIGS. 1B-1E illustrate inhalationdetection systems according to embodiments of the disclosure that senseairflow by detecting pressure differentials across a flow restriction.As will be discussed in further detail below with reference to FIGS. 2A,2C, and 3A, pressure sensors may be located within the droplet deliverydevice of the disclosure with a restriction that is internal to thedevice, e.g., within aerosol delivery mouthpiece tube. For instance,FIG. 1B is an example where the restriction is internal to the devicetube, and FIG. 1C, the restriction is at the air inlet laminar flowelement. The pressure is sensed as the differential between the interiorof the device tube and the pressure outside the tube. FIG. 1D is ascreen capture of an exemplary pressure sensor response to an inhaledbreath of a ˜1 second duration. FIG. 1E-1, FIG. 1E-2, and FIG. 1E-3illustrate exemplary differential pressure sensor designs and assembliesonto a device board (FIG. 1E-1). The sensor may have pneumaticconnection through the hole in the printed circuit board (PCB) and maybe mounted either on the main PCB, as shown below on scheme (FIG. 1E-2),or on a daughter board as shown on scheme (FIG. 1E-3).

Once activated, the droplet delivery device of the disclosure may beactuated to delivery an ejected stream of droplets for any suitable timesufficient to deliver the desired dosage. For instance, thepiezoelectric actuator may be activated to the oscillate the apertureplate to thereby generate the ejected stream of droplets for a shortburst of time, e.g., one tenth of a second, or for sever seconds, e.g.,5 second. In certain embodiments, the droplet delivery device may beactivated to generate and deliver the ejected stream of droplets, e.g.,for up to about 5 seconds, up to about 4 seconds, up to about 3 seconds,up to about 2 seconds, up to about 1 second, between about 1 second andabout 2 seconds, between about 0.5 seconds and 2 seconds, etc.

In certain embodiments, any suitable differential pressure sensor withadequate sensitivity to measure pressure changes obtained duringstandard inhalation cycles may be used, e.g., ±5 SLM, 10 SLM, 20 SLM,etc. For instance, pressure sensors from Sensirion, Inc., SDP31 or SDP32(U.S. Pat. No. 7,490,511 B2) are particularly well suited for theseapplications.

In certain embodiments of the present disclosure, the signal generatedby the pressure sensors provides a trigger for activation and actuationof the ejector mechanism of the droplet delivery device at or during apeak period of a patient's inhalation (inspiratory) cycle and assuresoptimum deposition of the ejected stream of droplets and delivery of themedication into the pulmonary airways of the user.

In addition, an image capture device, including cameras, scanners, orother sensors without limitation, e.g. charge coupled device (CCD), maybe provided to detect and measure the ejected aerosol plume. Thesedetectors, LED, delta P transducer, CCD device, all provide controllingsignals to a microprocessor or controller in the device used formonitoring, sensing, measuring and controlling the ejection of fluid andreporting patient compliance, treatment times, dosage, and patient usagehistory, etc., via Bluetooth, for example.

In certain aspects of the disclosure, the ejector mechanism, reservoir,and housing/mouthpiece function to generate a plume or aerosol of fluidwith droplet diameters less than 5 um. As discussed above, in certainembodiments, the reservoir and ejector mechanism are integrated to forma combination reservoir/ejector mechanism module which comprises thepiezoelectric actuator powered by electronics in the device housing anda drug reservoir which may carry sufficient fluid for just a few orseveral hundred doses of medicament.

In certain embodiments, as illustrated herein, the combination modulemay have a pressure equalization port or filter to minimize leakageduring atmospheric pressure changes such as on a commercial airliner.The combination module may also include components that may carryinformation read by the housing electronics including key parameterssuch as actuator frequency and duration, drug identification, andinformation pertaining to patient dosing intervals. Some information maybe added to the module at the factory, and some may be added at thepharmacy. In certain embodiments, information placed by the factory maybe protected from modification by the pharmacy. The module informationmay be carried as a printed barcode or physical barcode encoded into themodule geometry (such as light transmitting holes on a flange which areread by sensors on the housing). Information may also be carried by aprogrammable or non-programmable microchip on the module whichcommunicates to the electronics in the housing via the piezoelectricpower connection. For example, each time the device is turned on, thecartridge may be sent minimal voltage, e.g., five volts through thepiezoelectric power connection which causes the data chip to send alow-level pulse stream back to the electronics via the same powerconnection.

By way of example, module programming at the factory or pharmacy mayinclude a drug code which may be read by the device, communicated viaBluetooth to an associated user smartphone and then verified as correctfor the user. In the event a user inserts an incorrect, generic,damaged, etc., module into the device, the smartphone might be promptedto lock out operation of the device, thus providing a measure of usersafety and security not possible with passive inhaler devices. In otherembodiments, the device electronics can restrict use to a limited timeperiod (perhaps a day, or weeks or months) to avoid issues related todrug aging or the gradual buildup of contamination on the apertureplate.

An airflow sensor located in the device aerosol delivery tube measuresthe inspiratory and expiratory flow rates flowing in and out of themouthpiece. This sensor is placed so that it does not interfere withdrug delivery or become a site for collection of residue or promotebacterial growth or contamination. A differential (or gage) pressuresensor downstream of a flow restrictor (e.g., laminar flow element)measures airflow based upon the pressure differential between the insideof the mouthpiece relative to the outside air pressure. Duringinhalation (inspiratory flow) the mouthpiece pressure will be lower thanthe ambient pressure and during exhalation (expiratory flow) themouthpiece pressure will be greater than the ambient pressure. Themagnitude of the pressure differential during an inspiratory cycle is ameasure of the magnitude of airflow and airway resistance at the airinlet end of the aerosol delivery tube.

In one embodiment, referring to FIG. 2A, an exemplary droplet deliverydevice 100 is illustrated including an power/activation button 132; anelectronics circuit board 102; an ejector mechanism 104 including apiezoelectric actuator 106 and an aperture plate 108; a reservoir 110,which may include an optional filter 110 a on a surface thereof; and apower source 112 (which may optionally be rechargeable) electronicallycoupled to the piezoelectric actuator 106. In certain embodiments, thereservoir 110 may be coupled to or integrated with the ejector mechanism104 to form a combination drug reservoir/ejector mechanism module (seeFIG. 4A-4B) that may be replaceable, disposable or reusable. Dropletdelivery device 100 further includes power source 112, which whenactivated, e.g., by pressure sensor 122 upon sensing a pre-determinedchange in pressure within the device, will energize the piezoelectricactuator 106 to vibrate the aperture plate 108 to cause an ejectedstream of droplets to be ejected through the aperture plate 108 in apredefined direction. Droplet delivery device 100 may further includesurface tension plate 114 to, at least in part, direct and focus fluidto the aperture plate 108, as described further herein.

The components may be packaged in a housing 116, which may be disposableor reusable. The housing 116 may be handheld and may be adapted forcommunication with other devices via a Bluetooth communication module118 or similar wireless communication module, e.g., for communicationwith a subject's smart phone, tablet or smart device (not shown). In oneembodiment, laminar flow element 120 may be located at the air entryside of the housing 116 to facilitate laminar airflow across the exitside of aperture plate 108 and to provide sufficient airflow to ensurethat the ejected stream of droplets flow through the device during use.Aspects of the present embodiment further allows customizing theinternal pressure resistance of the droplet delivery device by allowingthe placement of laminar flow elements having openings of differentsizes and varying configurations to selectively increase or decreaseinternal pressure resistance, as will be explained in further detailherein.

Droplet delivery device 100 may further include various sensors anddetectors 122, 124, 126, and 128 to facilitate device activation, sprayverification, patient compliance, diagnostic mechanisms, or as part of alarger network for data storage, big data analytics and for interactingand interconnected devices used for subject care and treatment, asdescribed further herein. Further, housing 116 may include an LEDassembly 130 on a surface thereof to indicate various statusnotifications, e.g., ON/READY, ERROR, etc.

Referring more specifically to FIG. 2B, an enlargement of ejectormechanism 104 in accordance with an embodiment of the disclosure isillustrated. The ejector mechanism 104 may generally include apiezoelectric actuator 106, an aperture plate 108, which includes aplurality of openings 108 a formed through its thickness. A surfacetension plate 114 may also be positioned on the fluid facing surface ofthe aperture plate, as described in more detail herein. Thepiezoelectric actuator 106 is operable to oscillate, e.g., at itsresonant frequency, the aperture plate 108 to thereby generate anejected stream of droplets through the plurality of openings 108 a. Incertain embodiments, openings 108 a and ejector mechanism 104 may beconfigured to generate an ejected stream of droplets having a MMAD of 5μm or less.

The airflow exit of housing 116 of the droplet delivery device 100 ofFIG. 2A through which the ejected stream of droplets exit as they areinhaled into a subject's airways, may be configured and have, withoutlimitation, a cross sectional shape of a circle, oval, rectangular,hexagonal or other shape, while the shape of the length of the tube,again without limitation, may be straight, curved or have a Venturi-typeshape.

In another embodiment (not shown), a mini fan or centrifugal blower maybe located at the air inlet side of the laminar flow element 120 orinternally of the housing 116 within the airsteam. The mini fangenerally may provide additional airflow and pressure to the output ofthe airstream. For patients with low pulmonary output, this additionalairstream may ensure that the ejected stream of droplets is pushedthrough the device into the patient's airway. In certainimplementations, this additional source of airflow ensures that theejector face is swept clean of the ejected droplets and also providesmechanism for spreading the droplet plume into an airflow which createsgreater separation between droplets. The airflow provided by the minifan may also act as a carrier gas, ensuring adequate dose dilution anddelivery.

With reference to FIG. 2C, another implementation of a droplet deliverydevice of the disclosure is illustrated in an exploded view. Again, likecomponents are indicated with like reference numbers. Droplet deliverydevice 150 is illustrated with a top cover 152, which provides a coverfor the aerosol delivery mouthpiece tube 154 and interfaces withreservoir 110, a base handle 156, an activation button 132, and bottomcover for the handle 158.

A series of colored lights powered by an LED assembly are located in thefront region of the ejector device. In this embodiment, the LED assembly130, including, e.g., four LED's, 130A, and an electronics board 130B,on which the LED assembly 130 is mounted and provides an electricalconnection to the main electronics board 102. The LED assembly 130 mayprovide the user with immediate feedback on functions such as, power, ONand OFF, to signal when breath activation occurs (as described furtherherein), to provide the user with feedback as to when an effective orineffective dispense of a dose is delivered (as described furtherherein), or to provide other user feedback to maximize patientcompliance.

The laminar flow element 120 is located opposite the patient use end ofthe mouthpiece tube 154, and a differential pressure sensor 122,pressure sensor electronics board 160, and pressure sensor O-ring 162are located nearby.

The remaining components detailed in FIG. 2C are located in the devicehandle 156, which include the mount assembly 164 for power source 112(e.g., three, AAA batteries), top and bottom battery contacts, 112A,112B, and audio chip and speaker, 166A, 166B.

Again, with reference to FIG. 2C, a Bluetooth communication module 118or similar wireless communication module is provided in order to linkthe droplet delivery device 150 to a smartphone or other similar smartdevices (not shown). Bluetooth connectivity facilitates implementationof various software or App's which may provide and facilitate patienttraining on the use of the device. A major obstacle to effective inhalerdrug therapy has been either poor patient adherence to prescribedaerosol therapy or errors in the use of an inhaler device. By providinga real time display on the smartphone screen of a plot of the patient'sinspiratory cycle, (flow rate versus time) and total volume, the patientmay be challenged to reach a goal of total inspiratory volume that waspreviously established and recorded on the smartphone during a trainingsession in a doctor's office. Bluetooth connectivity further facilitatespatient adherence to prescribed drug therapy and promotes compliance byproviding a means of storing and archiving compliance information, ordiagnostic data (either on the smartphone or cloud or other largenetwork of data storage) that may be used for patient care andtreatment.

The aerosol delivery mouthpiece tube may be removable, replaceable andsterilizable. This feature improves sanitation for drug delivery byproviding means and ways to minimize buildup of aerosolized medicationwithin the mouthpiece tube by providing ease of replacement,disinfection and washing. In one embodiment, the mouthpiece tube may beformed using sterilizable and transparent polymer compositions such aspolycarbonate, polyethylene or polypropylene, and not limited byexample. With reference to FIG. 2D, a topview of an exemplary aerosoldelivery mouthpiece tube 154 is illustrated, which includes a circularport 168 through which the aerosol spray passes from the ejectormechanism (not shown), as well as the location of a slot 170 thataccommodates the pressure sensor (not shown). Materials selection forthe aerosol delivery mouthpiece tube should generally allow effectivecleaning and have electrostatic properties that do not interfere with ortrap fluid droplets of interest. Unlike many spray devices with largerdroplets and higher dispense velocities, the mouthpiece of thedisclosure does not need to be long or specially shaped to reduce thespeed of large droplets that would otherwise impact the back of thepatients mouth and throat.

In other embodiments, the internal pressure resistance of the dropletdelivery device may be customized to an individual user or user group bymodifying the mouthpiece tube design to include various configurationsof air aperture grids or openings, thereby increasing or decreasingresistance to airflow through the device as the user inhales. Forinstance, with reference to FIG. 2E, an exemplary aperture grid 172 atthe mouthpiece tube opening is illustrated. However, different airentrance aperture sizes and numbers may be used to achieve differentresistance values, and thereby different internal device pressurevalues. This feature provides a mechanism to easily and quickly adaptand customize the airway resistance of the droplet delivery device tothe individual patient's state of health or condition.

Referring to FIGS. 3A-3C, another implementation of a droplet deliverydevice of the disclosure is illustrated. Again, like components areillustrated with like reference numbers. In the embodiment shown,droplet ejector device 200 may include an ejector mechanism 104 that isvertically oriented. As illustrated, droplet ejector device 200 iscomprised of electronics circuit board 102; ejector mechanism 104including piezoelectric actuator 106 and aperture plate 108 (FIG. 3B);surface tension plate 114 (FIG. 3C), reservoir 110, which may optionallybe coupled to the ejector mechanism 104 to form a combinationreservoir/ejector mechanism module that is replaceable, disposable orreusable, power source 112 that is coupled to the piezoelectric actuator106, and activation button 132. The power source 112, when activatedwill energize the piezoelectric actuator 106 to vibrate the apertureplate 108 to cause a stream of ejected droplets to be ejected throughthe aperture plate 108 in a predefined direction. The components may bepackaged in a housing 116, which may be disposable or reusable. Thehousing 116 may be handheld and may be adapted for communication withother devices. For example, Bluetooth module 118 may be adapted forcommunication with the patient's smart phone, tablet or smart device.Device 200 may include one or more sensor or detector means 122, 124,126 for device activation, spray verification, patient compliance,diagnostic means, or part of a larger network for data storage, and forinteracting and interconnected devices used for subject care andtreatment. The device may be unitary, two pieces or three pieces, e.g.,with a disposable combination reservoir/ejector mechanism module, adisposable mouthpiece and disposable or reusable electronics unit.

Any suitable material may be used to form the housing of the dropletdelivery device. In particular embodiment, the material should beselected such that it does not interact with the components of thedevice or the fluid to be ejected (e.g., drug or medicament components).For example, polymeric materials suitable for use in pharmaceuticalapplications may be used including, e.g., gamma radiation compatiblepolymer materials such as polystyrene, polysulfone, polyurethane,phenolics, polycarbonate, polyimides, aromatic polyesters (PET, PETG),etc.

In certain aspects of the disclosure, an electrostatic coating may beapplied to the one or more portions of the housing, e.g., inner surfacesof the housing along the airflow pathway, to aid in reducing depositionof ejected droplets during use due to electrostatic charge build-up.Alternatively, one or more portions of the housing may be formed from acharge-dissipative polymer. For instance, conductive fillers arecommercially available and may be compounded into the more commonpolymers used in medical applications, for example, PEEK, polycarbonate,polyolefins (polypropylene or polyethylene), or styrenes such aspolystyrene or acrylic-butadiene-styrene (ABS) copolymers.

As mentioned above, in certain configurations of the disclosure, thereservoir and ejector mechanism may be integrated together into acombination reservoir/ejector mechanism module that may be removableand/or disposable. In certain embodiments, the combinationreservoir/ejector mechanism module may be vertically orientated suchthat the surface tension plate may facilitate fluid contact between thefluid in the reservoir and the fluid contact surface of the apertureplate. In other configurations, the combination reservoir/ejectormechanism module be horizontally oriented within the device andpositioned such that the fluid within the reservoir is in constantcontact with the fluid contact surface of the aperture plate.

For instance, with reference to FIGS. 4A-4B, the combinationreservoir/ejector mechanism module 400 is illustrated including thepiezoelectric actuator 106, aperture plate 108, surface tension plate114, a guide 402 which facilitates and aligns insertion of the module400 onto the ejector device (not shown), filter 404, and ejectormechanism housing 414. In certain embodiments, filter 404 is comprisedof a sandwich structure in which a polymer, metal or other compositematerial structure includes a micro-size aperture 404B located betweentwo superhydrophobic filters 404A, such as those provided by NittoDenko, Temish, high performance breathable porous membranes. FIG. 4A-1shows an exploded view, FIG. 4A-2 shows a top view, FIG. 4A-3 shows across sectional view, and FIG. 4A-4 shows an enlarged view of a portionof a module and mechanism for mechanical mounting of the ejectormechanism to the reservoir, in accordance with an embodiment of thedisclosure. FIG. 4B shows a side view of an exemplary superhydrophobicfilter and micron-sized aperture for restricting evaporation, inaccordance with an embodiment of the disclosure.

In certain embodiments, module 400 may further include a seal 404C,which seals the fill hole used to dispense fluid into the ampule. Othercomponents include a polymer cap 406 which seals the top of the ampule,a housing cup 408 which includes the surface tension plate 114, anO-ring structure 410 which supports the aperture plate 108 andpiezoelectric actuator 106, which make electrical contact to theelectronics through connector pins 412.

Also included in the module 400 is an optional bar code (not shown)which may provide electrical contact and electrical feed to thepiezoelectric actuator 106, as well as provide information on the drugtype, initial drug volume, concentration, e.g.; dosing information suchas single or multiple dosing regimens, dosing frequency and dosingtimes. Additional information that may be included on the barcode whichmay identify the type of aperture plate, target droplet sizedistribution and target site of action in the pulmonary airways or body,in general. Alternatively, this information may be carried on anelectronic chip embedded in the module which can be read either via awireless connection or via a signal carried by the piezoelectric powerconnection or via one or more additional physical contacts. Otherinformation included on the barcode or chip may provide critical drugcontent information or cartridge identification which may preventimproper use of the device or accidental insertion of expired orimproper medication, for example.

In certain embodiments, the droplet delivery devices of the disclosuremay further include an ejector closure mechanism, which may provide aclosure barrier to restrict evaporation of reservoir fluid through theaperture plate and may provide a protective barrier from contaminationfor the aperture plate and reservoir. As will be understood by those ofskill in the art, together with the reservoir, the ejector closuremechanism may provide for a protective enclosure of thereservoir/ejector mechanism module to thereby minimize evaporative loss,contamination, and/or intrusion of foreign substances into the reservoirduring storage.

With reference to FIGS. 5A-5B, an exemplary ejector closure mechanism502 is illustrated at the ejector spray exit port 504 (FIG. 5A showingejector closure mechanism 502 in an open configuration and FIG. 5Bshowing ejector closure mechanism 502 in a closed configuration). Theejector closure mechanism can be either manually opened and closed orelectronically actuated. In certain embodiments, the ejector closuremechanism may include one or more sensors to prevent operation of theejector mechanism when the ejector closure mechanism is not open. Inother embodiments, the ejector closure mechanism may be automaticallypowered when the droplet delivery device is powered one, and/or theejector closure mechanism may automatically close at a predeterminedtime interval after actuation of a dose, e.g., 15 seconds, 30 seconds, 1minute, 5 minutes, 10 minutes, etc.

With reference to FIGS. 5C-5E, a more detailed view of an exemplaryejector closure mechanism is provided. Removal of housing top cover 152exposes the ejector closure actuation mechanism 506 which includes aclosure guide 508, sliding seal plate 510, and a motor mechanism 512,which may open and close the sliding seal plate 510 as the motormechanism 512 is activated. Any suitable miniature motor mechanism maybe used, e.g., a thread and screw motor that is piezoelectric driven andactuated such as an ultrasonic swiggle motor from SI ScientificInstruments (www.si-gmbh.de). This mechanism may provide assurance ofmaintaining a fully sealed reservoir/ejector mechanism module to therebyminimize evaporative losses through the aperture plate or contaminationof the aperture plate. FIGS. 5F-5G provide a more detailed, explodedview of the ejector closure mechanism. The sliding seal plate 510 andclosure guide 508 are shown in an exploded view.

As described herein, the droplet delivery device of the disclosuregenerally may include a laminar flow element located at the air entryside of the housing. The laminar flow element, in part, facilitateslaminar airflow across the exit side of aperture plate and providessufficient airflow to ensure that the ejected stream of droplets flowsthrough the droplet delivery device during use. The laminar flow elementallows for customization of internal device pressure resistance bydesigning openings of different sizes and varying configurations toselectively increase or decrease internal pressure resistance.

In certain embodiments, the laminar flow element is designed andconfigured in order to provide an optimum airway resistance forachieving peak inspirational flows that are required for deep inhalationwhich promotes delivery of ejected droplets deep into the pulmonaryairways. Laminar flow elements also function to promote laminar flowacross the aperture plate, which also serves to stabilize airflowrepeatability, stability and insures an optimal precision in thedelivered dose.

Without intending to be limited by theory, in accordance with aspects ofthe disclosure, the size, number, shape and orientation of holes in thelaminar flow element of the disclosure may be configured to provide adesired pressure drop within the droplet delivery device. In certainembodiments, it may be generally desirable to provide a pressure dropthat is not so large as to strongly affect a user's breathing orperception of breathing.

In this regard, FIG. 6A illustrates the relationship betweendifferential pressure and flow rate through exemplary laminar flowelements of the disclosure as a function of aperture hole diameter (0.6mm, 1.6 mm and 1.9 mm), while FIG. 6B illustrates differential pressureas a function of flow rates through the laminar flow elements of thedisclosure as a function of number of holes (29 holes, 23 holes, 17holes). Laminar flow elements are mounted on droplet delivery devicessimilar to that provided in FIG. 2C.

Referring to FIG. 6C, the flow rate verses differential pressure as afunction of hole size is shown to have a liner relationship, when flowrate is plotted as a function of the square root of differentialpressure. The number of holes is held constant at 17 holes. These dataprovide a manner to select a design for a laminar flow element toprovide a desired pressure resistance, as well as provide a model forthe relationship between flow rate and differential pressure, asmeasured in a droplet delivery device similar to that provided in FIG.2C.

Inspiratory Flow Rate (SLM) = C(SqRt) (Pressure(Pa)) Hole Size (mm)Pressure at Flow at Equation Element # (17 holes) 10 slm (Pa) 1000 PaConstant (C) 0 1.9 6 149.56 4.73 1 2.4 2.1 169.48 5.36 2 2.7 1.7 203.166.43 3 3 1.3 274.46 8.68

Referring to FIG. 6D, a non-limiting exemplary laminar flow element isillustrated with 29 holes, each 1.9 mm in diameter. However, thedisclosure is not so limited. For example, the laminar flow element mayhave hole diameters ranging from, e.g., 0.1 mm in diameter to diametersequal to the cross sectional diameter of the air inlet tube (e.g., 0.5mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5.5mm, 6 mm, 6.5 mm, etc.), and number of holes may range from 1 to thenumber of holes, for example, to fill the laminar flow element area(e.g., 30, 60, 90, 100, 150, etc.). The laminar flow element may bemounted at the air inlet side of a droplet delivery device as describedherein.

In certain implementations, the use of laminar flow elements havingdifferent sized holes, or the use of adjustable apertures may berequired in order to accommodate the differences among the lungs andassociated inspiratory flow rates of young and old, small and large, andvarious pulmonary disease states. For example, if the aperture isadjustable by the patient (perhaps by having a slotted ring that can berotated), then a method may be provided to read the aperture holesetting and lock that position to avoid inadvertent changes of theaperture hole size, hence the flow measurement. Although pressuresensing is an accurate method for flow measurement, other embodimentsmay use, e.g., hot wires or thermistor types of flow rate measurementmethods which lose heat at a rate proportional to flow rate, movingblades (turbine flow meter technology) or by using a spring-loadedplate, without limitation of example.

As described herein, the droplet delivery device of the disclosuregenerally may include an ejector mechanism including a piezoelectricactuator coupled directly or indirectly to an aperture plate, theaperture plate having a plurality of openings formed through itsthickness. The plurality of openings may have a variety of shapes, sizesand orientations. With reference to FIGS. 7A-7B, exemplary ejectormechanisms of the disclosure are illustrated. FIG. 7A illustratescomponents of one configuration of an ejector mechanism of thedisclosure wherein the piezoelectric actuator 106 may be directlycoupled to the aperture plate, and FIG. 7B illustrates anotherconfiguration of an ejector mechanism of the disclosure wherein thepiezoelectric actuator 106 may be indirectly coupled to the apertureplate 108 via an actuator plate 108 b. In the embodiment of FIG. 7B, thepiezoelectric actuator 106 is directly coupled to the actuator plate 108b, which is then directly coupled to the aperture plate 108. Uponactivation, piezoelectric actuator 106 oscillates the actuator plate 108b, which then in turn oscillates the aperture plate 108 to generate theejected stream of droplets.

The aperture plate may have any suitable size, shape or material. Forexample, the aperture plate may have a circular, annular, oval, square,rectangular, or a generally polygonal shape. Further, is accordance withaspects of the disclosure, the aperture plate may be generally planar ormay have a concave or convex shape. In certain embodiments, the apertureplate may have a generally domed or half-spherical shape. By way ofnon-limiting example, with reference to FIG. 8A-8B, an exemplaryaperture plate 808 is illustrated wherein openings 808 a are located ina region having a generally domed-shape.

In this regard, in certain aspects of the disclosure, it wasunexpectedly found that improved ejector mechanism performance may beobtained with aperture plates having a generally domed-shape. Referringto FIGS. 10A-10B, a comparison of the medium damping influence of airverses distilled water on resonant frequency for planar (FIG. 10A)versus domed-shaped aperture plates (FIG. 10B) is provided. These plotssuggest that ejector mechanisms using domed-shaped aperture plates aremore stable and less sensitive to viscosity, and mass loading and mediumdamping effects, in comparison to ejector mechanism using planaraperture plates. Ejector mechanisms using domed-shaped aperture platesprovide improved performance by maintaining a stable and optimumresonance frequency. In this regard, a droplet delivery device of thedisclosure comprising an aperture plate having a generally domed shapewill deliver a more accurate, consistent, and verifiable dose to asubject, with a droplet size distribution that is suitable forsuccessful delivery of medication to the subject's pulmonary system.

Referring to FIG. 11, Digital Holographic Microscopy (DHM) was appliedto identify the resonance frequencies of a domed-shaped aperture platein accordance with an aspect of the disclosure. Amplitude ofdisplacement at resonance, and capture of the instantaneous Eigenmodeshapes for the vibrating, circular, domed-shaped aperture plates areillustrated, as well as the corresponding graph of the frequency sweepversus amplitude of displacement for the dome-shaped aperture plate from50 kHz to 150 kHz and excitation voltage; 5 Vpp. With reference toinsets of FIG. 11-1-FIG. 11-3, the Eigenmode shapes associated withresonance frequencies 59 kHz (FIG. 11-1), 105 kHz (FIGS. 11-2), and 134kHz (FIG. 11-3), are shown in call-out images for the domed-shapedaperture plate. Unlike the predicted and experimentally verifiedEigenmodes associated with piezoelectric actuated circular and planaraperture plates, the Eigenmodes associated with domed-shaped apertureplates do not change shape or Eigenmodes with increasing excitationfrequency, but retain the domed-shape of the resting aperture platemorphology.

In certain implementations of the disclosure, design parameters thatdefine the domed shape geometry of an exemplary aperture plate includedome height, active area (region including the plurality of openings),and shape and geometry of the dome. Referring to FIG. 12A-12B, the domeheight (h) and dome diameter (d) are defined by the arc formed bydrawing a circle whose diameter includes the verteces of the perimeterof the active area (FIG. 12A). The resulting equation which defines theparameters dome height and active area (base of dome) are shown in FIG.12B, which illustrates the relation between aperture plate dome heightand active area diameter.

As indicated in the table below, performance comparisons of apertureplates with planar versus domed shapes with regard to droplet generationefficiency as measured by ml of fluid ejected per minute shows that thedomed shape provides a significant improvement in performance.

Active Area Active Exit Hole Drive Excitation Ejected diameter AreaDiameter Frequency Voltage Volume (mm) (mm2) (um) (kHz) (Vpp) (ml/min)Planar 6 28.27 4 113 40 0.5 shape Domed 2 3.14 3 109 30 0.7 shape

These data indicate that the planar surface ejects 0.5 mL/min over anactive surface area of 28.3 mm² footprint (area) and the domed surfaceejects 0.7 mL/min from just a 3.1 mm² active surface area footprint forsimilar openings. In other words, the domed surface ejects 12.6 timesmore mass per unit area of active surface area footprint as compared tothe planar surface.

The aperture plate of the disclosure may be formed from any suitablematerial known in the art for such purposes. By way of non-limitingexample, the aperture plate may be composed of a pure metal, metal alloyor high modulus polymeric material, such as, and not limited by example,Ni, NiCo, Pd, Pt, NiPd, or other metals or alloy combinations, polyetherether ketone (PEEK), polyimide (Kapton), polyetherimide (Ultem),polyvinylidine fluoride (PVDF), ultra-high molecular weight polyethylene(UHMWPE), as well as a range of filler materials blended into polymersto enhance physical and chemical properties may be used for apertureplate designs and fabrication. Filler materials can include but are notlimited to glass and carbon nanotubes. These materials may be used toincrease the yield strength and the stiffness or modulus of elasticity.In one embodiment, the aperture plate may be obtained from OptnicsPrecision Co. LTD. model No. TD-15-05B-OPT-P90-MED

In certain embodiments, it may be desirable to provide coatings orsurface modification to the aperture plates (chemical or structural) inorder to enhance microfluidic properties, render surfaces eitherhydrophilic or hydrophobic or render surfaces antimicrobial.

In certain implementations of the disclosure an aperture plate formedfrom the high modulus polymeric may be processed to reduce residualstresses that may accumulate in its morphology and thickness during filmformation and fabrication. For example, annealing of PEEK film is astandard procedure suggested by Victrex to obtain optimizedcrystallinity and to allow relaxation of intrinsic stresses.(www.victrex.com). The systems and methods for releasing residualstresses in high modulus polymeric materials may provide increased yieldstrength of an aperture plate formed from such materials so as tooptimize its stability in the oscillations of the aperture plate as wellas minimize plastic deformation of the entrance and exit orificegeometries of the nozzle plate during actuation. In this regard, thesystems and methods for releasing residual stresses in the high moduluspolymeric aperture plate may insure delivery and administration of arepeatable, consistent dose of medicament.

Further, PEEK, due to its desirable mechanical performance in dynamicloading and its resistance up to high temperatures, is easily lasermicromachined and excimer laser ablated, making it a suitable materialfor fabrication of aperture plates. By way of a non-limiting example,laser excimer treatment of polymer surfaces, and PEEK surfaces inparticular, may be used for surface treatment of PEEK aperture plates inorder to improve adhesive bonding of the piezoelectric ceramic to thePEEK aperture plate. (P. Laurens, et al., Int. J. Adhes. (1998) 18). Inaddition, laser ablation and fine machining of PEEK may be used to formparallel grooves or other surface structures, which may lead to theformation of superhydrophobic regions on selected surface areas of thePEEK aperture plates, which may inhibit the drug solution or suspensionfrom wetting selected regions of the aperture plate.

By way of non-limiting example, the plurality of openings may range inaverage diameter from about 1 μm to about 200 μm, about 2 μm to about100 μm, about 2 μm to about 60 μm, about 2 μm to about 40 μm, about 2 μmto about 20 μm, about 2 μm to about 5 μm, about 1 μm to about 2 μm,about 2 μm to about 4 μm, about 10 μm to about 40 μm, about 10 μm toabout 20 μm, about 5 μm to about 10 μm, etc. Further, in certainembodiments, various openings on an aperture plate may have the same ordifferent sizes or diameters, e.g., some may have an average diameter ina range of about 1 μm to about 2 μm and others may have a diameter ofabout 2 μm to about 4 μm or about 5 μm to about 10 μm, etc. Forinstance, holes of differing sizes may be used to generate dropletswithin a varied size range to target different areas of the pulmonarysystem, e.g., to target the tongue, oral cavity, pharynx, trachea, upperairways, lower airways, deep lunges, and combinations thereof.

Aperture plate thickness may range from about 10 μm to about 300 μm,about 10 μm to about 200 μm, about 10 to about 100 μm, about 25 μm toabout 300 μm, about 25 μm to about 200 μm, about 25 μm to about 100 μm,etc. Further, the number of openings in the aperture plate may rangefrom, e.g., about 5 to about 5000, about 50 to about 5000, about 100 toabout 5000, about 250 to about 4000, about 500 to about 4000, etc. Itcertain embodiments, the number of openings may be increased ordecreased by increasing or decreasing the aperture plate pitch (i.e.,opening center-to-center distance). In this regard, an increase in thepacking density, i.e. reducing the pitch distance, and increasing thenumber of opening in the aperture plate leads to an increase in thetotal droplet ejected volume.

In certain implementations, the openings in the aperture plate may havea generally cylindrical shape, tapered, conical, or hour-glass shape. Incertain embodiments, the openings may have a generally fluted shape,with a larger opening at one surface of the aperture plate, a smalleropening at the opposite surface of the aperture plate, and a capillarytherebetween. The larger and smaller of the openings may be orientedtowards the fluid entrance or fluid exit surface of the aperture plate,as desired.

In the embodiment shown in FIG. 9, the aperture plate is oriented withthe larger opening oriented towards the fluid entrance, and the smalleropening oriented towards the fluid exit. Without intending to be limitedby theory, the aperture plate opening shape, capillary length, and thefluid viscosity determines resistance to flow through the aperture plateopening and can be optimized to provide efficient ejection of droplets.

Referring to FIG. 9, the openings in the aperture plate include a fluidentrance side opening whose diameter (D_(en)) is larger than thediameter of the fluid exit side opening (D_(ex)). The walls of the fluidentrance chamber are fluted and contoured such that the cross sectionalprofile of the entrance cavity form a radius of curvature (E_(c)) thatis equal to the aperture plate thickness (t) minus the capillary length(C_(L)) as defined by the following equation:

E _(c) =t−C _(L)

where the fluid entrance side opening diameter (D_(en)) is equal to 2×the entrance cavity radius of curvature, plus the fluid exit sideopening diameter (D_(ex)):

D _(en)=2(E _(c))+D _(ex)

In certain embodiments, optimization of the aspect ratio of the fluidentrance to the fluid exit diameters, in combination with capillarylengths, allows for formation of ejected droplets of fluids havingrelatively high viscosities.

Any suitable method may be used to manufacture the aperture plates andthe plurality of openings within the apertures plates, as may be knownin the art and as may suitable for the particular material of interest.By way of example, micromaching, pressing, laser ablation, LIGA,thermoforming, etc. may be used. In particular, laser ablation ofpolymers is an established process for industrial applications. Excimerlaser micromachining is particularly well suited for fabrication ofpolymeric aperture plates. However, the disclosure is not so limited andany suitable method may be used.

As described herein, the ejector mechanism of the disclosure alsocomprises a piezoelectric actuator. Piezoelectric actuators are wellknown in the art as electronic components used as sensors, dropletejectors or micro pumps, for example. When a voltage is applied across apiezoelectric material, the crystalline structure of the piezoelectricis affected such that the piezoelectric material will change shape. Whenan alternating electric field is applied to a piezoelectric material, itwill vibrate (contracting and expanding) at the frequency of the appliedsignal. This property of piezoelectric materials can be exploited toproduce effective actuators, to displace a mechanical load. As voltageis applied to a piezoelectric actuator, the resulting change in thepiezoelectric material's shape and size displaces the load.

As described herein, in certain aspects, the piezoelectric actuatordrives the oscillation of the aperture plate which produces thevibration that leads to the formation of the ejected stream of droplets.As an alternating voltage is applied to electrodes on the surface of thepiezoelectric actuator, the aperture plate oscillates and a stream ofdroplets are generated and ejected from the openings in the apertureplate along a direction away from the fluid reservoir.

The piezoelectric actuator may be formed from any suitable piezoelectricmaterial or combination of materials. By way of non-limiting example,suitable piezoelectric materials include ceramics that exhibit thepiezoelectric effect such as lead zirconate titanate (PZT),lead-titanate (PbTiO2), lead-zirconate (PbZrO3), or barium titanate(BaTiO3). Further, the piezoelectric actuator may have any suitable sizeand shape, so as to be compatible to oscillate the aperture plate. Byway of example, the piezoelectric actuator may have a generally annulusor ring shape, with a center opening that accommodates the active area(the region with the plurality of openings) of the aperture plate so asto allow the ejected stream of droplets to pass through the apertureplate.

In this regard, the use of axisymmetric piezoelectric actuators in theform of an annulus or ring to produce motion in a generally circularsubstrate plate for a variety of microfluidic applications is wellknown. A range of actuating voltages may be used as a periodic voltagesignal applied in a variety of waveforms, e.g., sinusoidal, square orother implementations, and the direction of the voltage differential maybe periodically reversed with the period of oscillation dependent on theresonant frequency of the piezoelectric material, for example to +15V to−15V, or a range peak-to-peak from 5V to 250V. In embodiments of thedisclosure, any suitable voltage signal and waveform may be applied toobtain the desired vibration and actuation of the aperture plate.

In piezoelectric actuated devices, the frequency and amplitude of thesignal driving the piezoelectric actuator has a significant effect onthe behavior of the piezoelectric actuator and its displacement. It isalso well known that when the piezoelectric element is at resonance, thepiezoelectric device will achieve the greatest displacement of itsmechanical load as well as achieve its highest operating efficiency. Inaddition, a variety of factors can impact the magnitude of displacementof the aperture plate. Factors such as the drive signal of thepiezoelectric actuator, the selected resonant frequency, and Eigen mode.Other factors include be include losses due to the piezoelectricmaterial which originate from its dielectric response to an electricalfield and its mechanical response to applied stress, or conversely, thecharge or voltage generation as a response to the applied stress.

In addition, the electrical and mechanical response of the piezoelectricactuator is also a function of fabrication methodology, theconfiguration and dimensions of the piezoelectric actuator, the positionand placement of the mechanical mounting of the piezoelectric actuatoronto the aperture plate and droplet delivery device, and thepiezoelectric electrode size and mounting, for example.

In another aspect of the disclosure, the reservoir may be configured toinclude an internal flexible drug ampoule to provide an airtight drugcontainer. With reference to FIG. 13, an exemplary reservoir 110 isillustrated including a flexible drug ampule 1302 packaged within a hardshell structure 1304, a lid closure 1306 that may include a screwclosure 1306A design (illustrated), a snap-in design or other alternateclosure system (not shown), and an ejector mechanism housing 104A. Thereservoir with flexible drug ampoule also include foil lidding 1308, aretainer ring 1310, which provides a rigid structure to support theflexible ampule as well as provide a slot to house an O-ring 1312, whichprevents leakage once the foil lidding 1308 is punctured to release itscontents. In certain embodiments, hard shell structure 1302 may includeone or more puncture elements (not shown) that are turned or otherwiseput into position to puncture foil lidding 1308 once reservoir 110 isput into position on the base of the droplet delivery device. Once thefoil lidding 1308 is perforated, the fluid within the flexible drugampule 1302 is able to flow out to the ejector mechanism.

In accordance with embodiments of the disclosure, the flexible drugampule may be formed using conventional form-fill-seal processes.Medical film materials that are available for its structure are shownbelow and include primarily micro-thick (e.g., 2-4 mil), low densitypolyethylene film.

Manufacturer Product Name Description The Dow LDPE 91003 Health+ Lowdensity polyethylene Chemical and LDPE 91020 film Company HealthLyondell Basell Purell PE 3420F Low density polyethylene Industries filmBorealis Group Bormed LE6609-PH Steam sterilizable polyethylene (above110 C.) Alcan Packaging Pouch laminate High barrier liddingPharmaceutical Product Code 92036 coextruded composite of PET, PackingInc. adhesive, aluminum, polyethylene Texas SV-300X 3 mil nylon, EVOH,poly Technologies coex SAFC Bioeaze Ethyl vinyl acetate film Biosciences

In another aspect of the disclosure, the droplet delivery device maycomprise a surface tension plate placed in proximity to the apertureplate on the fluid contact side of the aperture plate. As describedabove, the surface tension plate, at least in part, directs and focusesfluid to the aperture plate. More particularly, in certain embodiments,the surface tension plate may be on the on the fluid contact side of theaperture plate so as to provide for a uniform distribution of fluid ontothe aperture plate from the reservoir. In certain aspects of thedisclosure, as will be described in further detail herein, the distanceof placement of the surface tension plate from the aperture plateprovides for an optimization of performance of the ejector mechanism, asmeasured by ejected droplet mass rate.

Without intending to be limited, the surface tension plate may have agrid of perforations or holes of various sizes and configurations thatmay have circular, square, hexagonal, triangular or othercross-sectional shapes. In certain embodiments, the perforations orholes may be located along the perimeter, the center, or throughout theentirety of the surface tension plate. Any suitable size andconfiguration of perforations or holes may be used such that the desiredhydrostatic pressure and capillary action is achieved, as describedherein. FIGS. 14A-14B illustrate exemplary perforation or hole 1402configurations of various surface tensions plates 1400 of thedisclosure. Any suitable material known in the art for pharmaceuticalapplication may be used such that it does not interact to components ofthe droplet delivery device or the fluid to be delivered. For instance,pharmaceutically inert polymers known in the art for such purposes suchas polyethylenes and nylons may be used.

In certain embodiments, as illustrated in FIGS. 2A-2B, the surfacetension plate may be located in proximity to and behind the apertureplate, generally on the fluid contact side of the aperture plate.Further, in certain embodiments, the surface tension plate may beincluded as a component of a combination reservoir/ejector mechanismmodule.

Without intending to be limited by theory, the surface tension plategenerates hydrostatic pressure behind the aperture plate, whosemagnitude is dependent on the spacing between the surface tension plateand the aperture plate. For example, hydrostatic pressure exerted byfluid increases as the spacing between the surface tension plate and theaperture plate decreases. Furthermore, as the surface tension platedistance from the aperture plate decreases, there is an increase inhydrostatic pressure that is manifested as capillary rise in fluidbetween the surface tension plate and aperture plate. In this manner,the placement of a surface tension plate on the fluid contact side ofthe aperture plate can help provide for a constant supply of fluid tothe active area of the aperture plate, regardless of the orientation ofthe inhaler device.

Referring to FIG. 15B, ejected droplet mass rate, as ml/min, is measuredgravimetrically by weighing the filled reservoir before and afteractuation. The plot displayed in FIG. 15B represents averages of five(5), 2.2 second actuations (sprays) generated using an ejector mechanismincluding a surface tension plate 1400 with perforations 1402 configuredas illustrated in FIG. 15A and a domed shaped aperture plate (notshown). The effect of polymer composition of the surface tension plateon ejector mechanism performance was also tested. Surface tension plateswere formed using nylon6 or acrylonitrile butadiene styrene (ABS)copolymer. These compositions were chosen in order to investigate theeffect of critical surface tension, water contact angle and spacingbetween the surface tension plate and aperture plate, on ejectormechanism spray performance.

Critical Surface Tension Water Contact Angle Material (dynes/cm)(degrees) Nylon6 43.9 62.6 ABS 38.5 80.9

As illustrated in FIG. 15B, surface tension plates composed of nylon6demonstrated an unexpected increase in droplet mass rate when placed 1.5mm away from the dome-shaped aperture plate, as compared to surfacetension plates composed of ABS.

While the droplet delivery devices of the disclosure are not so limited,based on surface energy differences between materials of construction,as well as the inverse relationship between hydrostatic forces anddistance between the surface tension plate and the aperture plate;surface tension plate distances greater than about 2 mm may not providesufficient capillary action or hydrostatic force to ensure a constantsupply of fluid to the aperture plate. As such, in certain embodiments,the surface tension plate may be placed within about 2 mm of theaperture plate, within about 1.9 mm of the aperture plate, within about1.8 mm of the aperture plate, within about 1.7 mm of the aperture plate,within about 1.6 mm of the aperture plate, within about 1.5 mm of theaperture plate, within about 1.4 mm of the aperture plate, within about1.3 mm of the aperture plate, within about 1.2 mm of the aperture plate,within about 1.1 mm of the aperture plate, within about 1 mm of theaperture plate, etc.

In another embodiment of the disclosure, the droplet delivery device mayinclude two or more, three or more, four or more reservoirs, e.g., amultiple or dual reservoir configuration. In certain embodiments, themultiple or dual reservoir may be a combination multiple or dualreservoir/ejector module configuration, which may be removable and/ordisposable. The multiple or dual reservoir can deliver multiplemedications, flavors, or a combination thereof for polypharmacy.

In certain aspects, this system and methods provides a multiple or dualreservoir configuration that can deliver multiple medications prescribedto a patient, and which may be delivered through the same device. Thismay be particularly useful for subjects that take medications formultiple indications, or that require multiple medications for the sameindication. In accordance with the disclosure, the droplet deliverydevice may be programmed to administer the proper medication in theproper dosage according to the proper administration schedule, e.g.,based on barcode or embedded chip information programmed at thepharmacy.

By way of non-limiting example, FIGS. 16A-16B illustrate an exemplarycombination dual reservoir/ejector mechanism module and droplet deliverydevice in accordance with an embodiment of the disclosure. As shown inFIG. 16B, droplet delivery device 1600 includes device base 1602(comprising a disposable mouthpiece and disposable or reusableelectronics unit) and combination dual reservoir/ejector mechanismmodule 1604. Combination dual reservoir/ejector mechanism module 1604 isshown in further detail in FIG. 16A, including surface tension plate1606, aperture plate 1608, piezoelectric actuator 1610, optional barcodeor embedded chip (e.g., to provide dosing instruction, medicationidentification, etc.), and module insertion guide 1614. As illustrated,each dual reservoir/ejector mechanism module is generally configuredwith similar components.

More specifically, the combination dual reservoir/ejector mechanismmodule may have aperture plates that are similar in design and able togenerate ejected droplets with similar droplet size distributions thatare targeted for similar regions of the pulmonary airways.Alternatively, use of multiple medications or polypharmacy, may requiredelivery of medications to different areas of the pulmonary airways.Under these circumstances, each reservoir of the dual reservoir/ejectormechanism module may have an aperture plate with different openingconfigurations (e.g., different entrance and/or exit opening sizes,spacings, etc.) to deliver different droplet size distributionstargeting different regions of the pulmonary airways.

In other embodiments, the disclosure also provides a single or dualdisposable/reusable drug reservoir/ejector module that can delivermultiple medications, flavors, or combinations thereof for polypharmacyin which the aperture plate may include openings with multiple sizeconfigurations (e.g., different entrance and/or exit opening sizes,spacings, etc.). Aperture plates with openings having multiple sizeconfigurations generate droplets of different size distributions,thereby targeting different regions of the pulmonary airways. Althoughmany-sized-hole combinations are possible, by way of non-limitingexample, various combinations and densities of openings having averageexit diameters of e.g., about 1 μm, about 1 μm, about 3 μm, about 4 μm,about 10 μm, about 15 μm, about 20 μm, about 30 μm, about 40 μm, etc.

By way of non-limiting example, one opening may have an average exitdiameter of 4 μm and an octagonal array of 8 larger openings having anaverage exit diameter of 20 μm. In this manner, the aperture plate maydeliver both larger droplets (about 20 μm in diameter) as well assmaller droplets (about 4 μm in diameter), which can target differentregions of the pulmonary airways and which, for example, maysimultaneously deliver flavors to the throat and medication to the deepalveolar passageways.

Another aspect of the present disclosure as described herein, providesdroplet delivery device configurations and methods to increase therespirable dose of an ejected stream of droplets by filtering andexcluding larger droplets (having a MMAD larger than about 5 μm) fromthe aerosol plume by virtue of their higher inertial force and momentum(referred to herein as “inertial filtering”). In the event that dropletparticles having MMAD larger than 5 μm are generated, their increasedinertial mass may provide a means of excluding these larger particlesfrom the airstream by deposition onto the mouthpiece of the dropletdelivery device. This inertial filter effect of the drug delivery deviceof the disclosure further increases the respirable dose provided by thedevice, thus providing improved targeting delivery of medication todesired regions of the airways during use.

Without intending to be limited by theory, aerosol droplets have aninitial momentum that is large enough to be carried by the droplet plumeemerging from the aperture plate. When a gas stream changes direction asit flows around an object in its path, suspended particles tend to keepmoving in their original direction due to their inertia. However,droplets having MMAD larger than 5 μm generally have a momentum that issufficiently large to deposit onto the sidewall of the mouthpiece tube(due to their inertial mass), instead of being deflected and carriedinto the airflow.

Inertial mass is a measure of an object's resistance to accelerationwhen a force is applied. It is determined by applying a force to anobject and measuring the acceleration that results from that force. Anobject with small inertial mass will accelerate more than an object withlarge inertial mass when acted upon by the same force.

To determine the inertial mass of a droplet particle, a force of F,Newtons is applied to an object, and the acceleration in m/s² ismeasured. Inertial mass, m, is force per acceleration, in kilograms.Inertial force, as the name implies is the force due to the momentum ofthe droplets. This is usually expressed in the momentum equation by theterm (ρv)v. So, the denser a fluid, and the higher its velocity, themore momentum (inertia) it has.

$P = \frac{{\pi\rho}\; {Vd}^{3}}{6}$ $F = \frac{d({mv})}{dt}$Momentum-p The product of the mass and velocity is known as the linearmomentum$p = {m \cdot {v\mspace{14mu}\left\lbrack {{kg}\frac{m}{s}} \right\rbrack}}$  The first derivation of the momentum with time is Force  $F = \frac{d({mv})}{dt}$   If m = m(t) and v = v(t) then the derivationis:  $F = {{{\frac{dm}{dt}v} + {m\frac{dv}{dt}}} = {{\frac{dm}{dt}v} + {m \cdot a}}}$N · s Angular Momentum- L$L = {{I \cdot {\omega \mspace{14mu}\left\lbrack {{kg}\frac{m^{2}}{s}} \right\rbrack}} = {\left\lbrack {N \cdot m \cdot s} \right\rbrack = \frac{J}{s}}}$J/s I-Moment of intertia

With reference to FIGS. 17A-B, FIG. 17A illustrates a negative imagerecorded of a stream of droplets generated by a droplet delivery devicesimilar to that of FIGS. 2A-2B. The image provides empirical evidencefor the mechanism for generating entrained air from ejected droplets asa consequence of the combined momentum transfer from the droplets to thesurrounding air and the large specific surface area of droplets 5 μm andless in diameter. Region 1 represents a region of laminar flow, whileregion 2 is an area of turbulent flow due to the generation of entrainedair. FIG. 17B illustrates inertial filtering provided by an exemplarydroplet delivery device of the disclosure for filtering and excludinglarger droplets from the aerosol plume. Droplets undergo a 90 degreechange in spray direction (4, 5) as droplets emerge from the ejectormechanism and are swept by the airflow (3) through the laminar flowelement before inhalation into the pulmonary airways. Larger dropletsabove 5 μm (6) are deposited on the sidewall of the mouthpiece tube viainertial filtering.

In certain embodiments, larger droplets may be allowed to pass throughthe droplet delivery device within the effects of inertial filtering orwith varied effects of inertial filtering. For instance, the incomingairstream velocity may be increased (e.g., through use of the mini-fandescribed herein) so larger droplet particles may be carried into thepulmonary airways. Alternatively, the exit angle of the mouthpiece tubemay be varied (increased or decreased) to allow for deposition ofdroplets of varying sizes on the sidewalls of the mouthpiece. By way ofexample, with reference to FIGS. 17C-17D, if the angle of the mouthpieceis changed, the larger or smaller droplets will deposit or pass throughthe mouthpiece with or without impacting on the sidewalls of themouthpiece. FIG. 17C illustrates an embodiment with a standard 90 degreeturn, while FIG. 17D illustrate a greater than 90 degree turn. Theembodiment of FIG. 17D would allow droplets having a slightly largerdiameter to pass without impacting on the sidewall of the mouthpiece.

In another aspect of the disclosure, in certain embodiments, the dropletdelivery devices provide for various automation, monitoring anddiagnostic functions. By way of example, as described above, deviceactuation may be provided by way of automatic subject breath actuation.Further, in certain embodiments, the device may provide automatic sprayverification, to ensure that the device has generated the proper dropletgeneration and provided to proper dosing to the subject. In this regard,the droplet delivery device may be provided with one or more sensors tofacilitate such functionality.

More specifically, in certain embodiments, the droplet delivery devicemay provide automatic spray verification via LED and photodetectormechanisms. With reference to FIGS. 2A-2C, an infra-red transmitter(e.g., IR LED, or UV LED<280 nm LED), 126 and infra-red or UV (UV with<280 nm cutoff) photodetector 124 are mounted along the droplet ejectionside of the device to transmit an infra-red or UV beam or pulse, whichdetects the plume of droplets and thereby may be used for spraydetection and verification. The IR or UV signal interacts with theaerosol plume and can be used to verify that a stream of droplets hasbeen ejected as well as provide a measure of the corresponding ejecteddose of medicament. Examples include but not limited to, infrared 850 nmemitters with narrow viewing angles of either, 8, 10 and 12-degrees,(MTE2087 series) or 275 nm UV LED with a GaN photodetector for aerosolspray verification in the solar blind region of the spectra.Alternatively in some applications, the sub 280 nm LEDs (e.g. 260 nmLEDs) can be used to disinfect the spacer tube 128.

By way of example, the concentration of a medicament in the ejectedfluid may be made, according to Beer's Law Equation (Absorbance=e L c),where, e is the molar absorptivity coefficient (or molar extinctioncoefficient) which is a constant that is associated with a specificcompound or formulation, L is the path length or distance between LEDemitter and photodetector, and c is the concentration of the solution.This implementation provides a measure of drug concentration and can beused for verification and a means and way to monitoring patientcompliance as well as to detect the successful delivery of medication.

Referring to FIGS. 18A-18B, results are illustrated from exemplarydroplet delivery devices including LEDs 126 and photodetectors 124 (withreference to FIGS. 2A-2C), and enabled with automatic spray verificationusing (FIG. 18A) deep red LED (650 nm) and/or (FIG. 18B) near IR LED(850 nm) laser. Correct generation of a stream of droplets may beconfirmed by aerosol plume measurement. By way of non-limiting example,aerosol plume measurement may be implemented at locations in the devicemouthpiece tube between the exit end of mouthpiece and the ejectormechanism, across the face of the ejector mechanism, or at bothpositions. The aerosol plume may be optically measured via lighttransmission across the diameter of the mouthpiece for an absorptionmeasurement, or by scattering with the photodetector at 90 degrees tothe optical illumination so that scattering from the aerosol plumeincreases the light received at the photodetector.

In yet other embodiments, spray verification and dose verification maybe achieved by formulating the fluid/drug to include a compound thatfluoresces (or the fluid/drug may naturally fluoresce). Upon delivery ofthe stream of droplets, the fluorescence may be measured using standardoptical means. The light source used for measurement may be modulated,to minimize the effects of external light. When mounted, so that thelight path is parallel to and directly across the aperture plate, thegeneration of droplets by the aperture plate may be directly measured.This direct measurement can allow direct confirmation that the apertureplate is primed and working correctly. When mounted between the dropletexit and the aperture plate, the aerosol plume may be monitored as itpasses through the droplet delivery device. The optical means may be anyconventional LED with a relatively narrow beam and a half-angle lessthan twenty degrees. Alternatively, a laser diode may be used to producea very narrow, collimated beam that will reflect off individualdroplets. Various wavelengths from the near UV to the near IR have beenused to successfully measure aerosol plume absorption in transmissionmode. By using very short wavelength LEDs that are less than 280 nm,interference from sunlight or other conventional light sources can beavoided by placing a filter on the detector than attenuates wavelengthslonger than 275 nm. Similarly, if a fluorescing material is added to thefluid/drug, an optical bandpass filter may be placed in front of thedetector in order to avoid interference from the stimulation light orexternal light. Restriction of the ambient light may also beaccomplished by utilizing vanes or shades as part of the air-restrictionaperture between the device and ambient air.

In another aspect of the disclosure, the droplet delivery device may beused in connection with or integrated with breathing assist devices suchas a mechanical ventilator or portable Continuous Positive AirwayPressure (CPAP) machine, to provide in-line dosing of therapeutic agentswith the breathing assistance airflow.

For example, mechanical ventilators with endo-tracheal (ET) tubes areused to block secretions from entering the lungs of an unconsciouspatient and/or to breathe for the patient. The ET tube seals to theinside of the trachea just below the larynx with an inflatable balloon.However, common undesirable side-effects that result from use ofmechanical ventilators include ventilator-assisted pneumonia (VAP),which occurs in about ⅓ of patients who are on ventilators for 48 hoursor more. As a result, VAP is associated with high morbidity (20% to 30%)and increased health care systems costs. (Fernando, et al., Nebulizedantibiotics for ventilation-associated pneumonia: a systematic reviewand meta-analysis. Critical Care 19:150 2015).

Tobramycin administration through the pulmonary route is generallyregarded as superior to intravenous administration for treating VAP,with nebulizers being typically used to deliver the antibiotics throughgeneration of a continuous stream of droplets into the ventilatorairflow. The main benefit of inhaled versus oral or intravenousadministered antibiotics is the ability to deliver a higherconcentration of the antibiotic directly into the lungs. However,continuous generation of nebulizer mist provides imprecise dosing thatcannot be verified between inhalation and exhalation cycles.

As such, with reference to FIG. 19, an embodiment of the disclosure isprovided wherein a droplet delivery device 1902 is placed in-line with aventilator 1900, (for example a GE Carescape R860). The droplet deliverydevice 1902 generates a stream of droplets as described herein, whichincludes a therapeutic agent such as tobramycin, that enters into theventilator airstream near to the patient end of the endotracheal tube1904. FIG. 19 provides an example of a standalone device 1902 operatingwith a ventilator 1900. The ventilator 1900 supplies a stream ofinhalation air 1900A and removes a stream of exhalation air 1900B inseparate tubes that merge to a single endotracheal tube 1904 close tothe patient to minimize mixing of inhalations and exhalations and deadvolume. The droplet delivery device 1902 may be placed close to thepatient end of the endotracheal tube 1904 in order to minimize loss ofdroplets that may stick to the tube sidewall. The patient end of theendotracheal tube 1904 is placed in a patient's throat and held in placewith a balloon near the end of the tube (not shown).

Actuation of the droplet delivery device is initiated at the start of aninhalation cycle. The droplet delivery device can be battery powered andself-initiating, breath actuated or connected to electronics that arepart of the ventilator. The system may be configured so that dosingfrequency and duration may be set either within the ventilator or thedevice. Similarly, droplet ejection timing and duration can bedetermined by the device or initiated by the ventilator. For example,the device may be programmed to dispense for half a second once everyten breaths on a continuous basis or perhaps once a minute. A device mayoperate in a standalone manner or communicate the timing of dispensesand flowrates to the ventilator by a direct electrical connection or viaBluetooth or a similar wireless protocol.

Another aspect of the disclosure provides a system which may also beused with conventional portable CPAP machines to deliver therapeuticagents, e.g., where continuous or periodic dosing during the course ofthe night is valuable. In another embodiment, the droplet deliverydevices of the disclosure many be used in connection with a portableCPAP machine to prevent and treat cardiac events during sleep.

Typically CPAP machines use a mask to supply positive air pressure to apatient while sleeping. Applications of the droplet delivery devices inconjunction with CPAP machines may provide an efficient method forcontinuous dosing of therapeutic agents such as antibiotics, cardiacmedications, etc., for outpatient treatment of diseases, conditions, ordisorders, such as pneumonia, atrial fibrillation, myocardialinfarction, or any disease, condition, or disorder where continuous orperiodic nighttime delivery of a medicine is desired.

In sleep apnea (SA) there are periods of not breathing and an associateddecline in blood oxygen level. Not surprisingly, cardiac failure or“heart attacks” are associated with sleep apnea. This association isthought to be due to both the stress on the heart related to low oxygenlevels and the increased stress on the heart as the body requiresincreased blood pressure and cardiac output from the heart.Additionally, there is increased risk of sleep apnea in older andoverweight adults. Thus those with SA have a higher risk of heartattacks than the general population because the SA stresses the heartand because the risk factors associated with SA are very similar to therisk factors for heart attacks.

The Journal of New England in 2016 published a four-year study of theeffects of CPAP on 2700 men with sleep apnea and found that CPAPsignificantly reduced snoring and daytime sleepiness and improvedhealth-related quality of life and mood. (R. Doug McEvoy, et al. CPAPfor Prevention of Cardiovascular Events in Obstructive Sleep Apnea, N.ENGL. J. MED 375; 10 nejm.org Sep. 8, 2016). However, the use of CPAPdid not significantly reduce the number of cardiac events. The articlenoted that “Obstructive sleep apnea is a common condition among patientswith cardiovascular disease, affecting 40 to 60% of such patients.”

Many of these cardiac events can be lessened by administration of theproper medication. For example, beta blockers such as Metoprolol canlessen atrial fibrillation and the effects of myocardial infarction tosufficient extent as to prevent death in such an episode.

In certain aspects of the disclosure, the need to lessen adverse cardiacevents in the population of people using CPAP devices by sensing thepresence of the event and administering an ameliorating drug viapulmonary delivery is addressed. Specifically, a cardiac event may bedetected by conventionally available means to detect and evaluatecardiac condition. These include heart rate monitors (such as electricalsensors held in place by an elastic band across the chest or opticalmonitoring at the earlobe, finger or wrist), automated blood pressurecuffs, or blood-oxygen saturation monitors on the finger or ear). Whenthe monitor detects an adverse condition a specific dose of appropriatedrug is administered by a droplet delivery device of the disclosure viathe CPAP tube or mask so that the drug is inhaled and carried to theblood stream via deep inhalation into the lung. Pulmonary administrationis optimized both by the generation of droplets less than 5 microns insize and delivery of the droplets at the beginning of an inhalationcycle.

Referring to FIG. 20, a schematic representation and example for the useof a system 2000 including droplet delivery device 2002 of thedisclosure with a CPAP machine 2004 to assist with cardiac events duringsleeping. In certain aspects of the disclosure described herein, thepatient is shown sleeping with a CPAP mask 2006 in place and pressurizedair is delivered to the mask 2006 by the CPAP machine 2004. Cardiaccondition is monitored by optical measurement of the heartbeat either atfinger, toe, ear lobe or the wrist (not shown). The droplet deliverydevice 2002 may be placed in-line with the tube 2008 between the CPAPmachine 2004 and the CPAP mask 2006, or alternative may be placed at theairflow entrance of CPAP mask 2006 (not shown). Breathing is monitoredby airflow measurement in the tube 2008 from the CPAP machine 2004 tothe CPAP mask 2006. Airflow rate and direction can be measured bymeasuring the pressure on either side of a screen which adds a slightamount of airflow restriction. Typically there will be continuouspositive airflow which increases in flow rate at inspiration. Acontroller detects abnormal cardiac condition such as an increase inatrial fibrillation and triggers ejection of droplets of ananti-arrhythmic drug at the start of an inhalation cycle as detected byairflow in the CPAP supply tube. Information may be recorded and storedin a patient's smartphone 2010, and various alerts may be sounded if acardiac event is detected (e.g., transmitted via Bluetooth or otherwireless communication methodology), if desired. Further, the patient'scondition and drug dispenses may be monitored via a smartphone app,providing the patient and his medical provider with an accurate recordof the patient's condition.

Other diseases commonly associated with sleep apnea, use of a mechanicalventilator, or a CPAP machine may also benefit from a system whichnon-invasively monitors patient condition and provides pulmonaryadministration of the appropriate ameliorating medication via a dropletdelivery device of the disclosure. For example, those with diabetesfrequently are concerned that low blood sugar from a slight insulinoverdose will lead to unconsciousness. In this case, abnormally lowheartrate, breathing or blood pressure can be detected and sugar orinsulin administered via droplets to the pulmonary system.

Examples Example A: Automatic Breath Actuation

Referring to FIGS. 1B-E, droplet delivery device configurations ofdisclosure are providing including various sensor orientation thatprovide for automatic breath actuation of the ejector mechanism andautomatic spray verification. The sensors trigger actuation of a aerosolplume during a peak period of a patient's inhalation cycle. In certainimplementations the coordination of a patient's peak period ofinhalation may assure optimum deposition of the aerosol plume andassociated drug delivery into the pulmonary airways of the patient.Although a number of arrangements are possible, FIG. 1B shows anexemplary sensor configuration. SDPx series (SDP31 or SDP32 pressuresensors) from Sensirion (www.sensirion.com) may be used.

Example B: Droplet Size Distribution

Droplet size distribution and related functionality was evaluated forexemplary droplet delivery devices of the disclosure, including AndersonCascade Impactor testing, total drug mass output rates, total drugrespirable mass, delivery efficiencies and reproducibility. FIGS.21A-21F provide a summary of the test results.

Test Design

A study was conducted at ARE Labs, Inc. to evaluate the aerosolcharacteristics and delivered dose of Albuterol sulfate using thePneuma™ inhaler device. The study was designed to evaluate deviceperformance of a single Pneuma™ inhaler. A series of three (3)individual tests were conducted with a new disposable drug cartridge foreach test. The testing platform utilizes an eight-stage nonviableAnderson Cascade Impactor (Thermo Fisher Scientific; Waltham, Mass.)equipped with a calibrated AALBORG model GFM47 mass flow meter (AALBORGInstruments and Controls; Orangeburg, N.Y.) for flow rate measurement. Avalved Gast rotary vane vacuum pump (Gast Manufacturing; Benton Harbor,Mich.) was used to

A droplet delivery device of the disclosure similar to that shown inFIGS. 2A-2C was tested in triplicate with a new reservoir charged with750 μl of 5000 mg/ml Albuterol sulfate for each of the three (3)conducted tests. A fraction of the drug (100 μl) was extracted from thestock preparation solution of the albuterol sulfate using a calibratedmicro pipette, diluted in mobile phase, and analyzed via HPLC for drugconcentration. At the conclusion of each test, the mouthpiece was rinsedwith mobile phase and collected for HPLC analysis to determine the massfraction of non-respirable aerosolized drug captured in the mouthpiecevia inertial filtering. Following each test, impactor stage samples wereextracted and recovered in solvent and analyzed for the activepharmaceutical ingredient (API) using a Dionex Ultimate 3000 nano-HPLCwith UV detection (Thermo Scientific, Sunnyvale, Calif.).

The cascade impactor testing procedure involved fitting the mouthpieceinto the Impactor USP throat with a mouthpiece connection seal. Thevacuum pump supplying sample air flow to the cascade impactor was turnedon and the pump control valves adjusted to supply 28.3 L/min total flowthrough the impactor and inhaler body during aerosol tests.

At the initiation of each test, a new reservoir was filled with 750 μlof the stock Albuterol sulfate solution with a calibrated micropipette.The device was connected to the impactor USB throat, turned on, andactuated ten (10) times for each test. At the conclusion of the testperiod, the device, impactor, and dilution air sources were turned off.The i mouthpiece was rinsed in order to extract drug, and all stages ofthe cascade impactor were rinsed with a quantity of appropriate solvent(HPLC mobile phase). Extracted samples were placed in labeled andsterile HPLC vials, capped, and analyzed for drug content via HPLC withUV detection. The mouthpiece was extracted of residual drug and analyzedfor drug content via HPLC to measure mouthpiece drug deposition inrelation to the total collected on the impactor stages.

All system flow rates and impactor sample flows were monitoredthroughout each test period. Following each test, the impactor slideswere placed in labeled sterile Petri dishes, and impactor stages wereextracted of drug using 2 ml of mobile phase applied with a calibratedmicropipette. All extracted samples from the mouthpiece and impactorwere placed in labeled sterile amber HPLC sample vials, and storedrefrigerated at approximately 2° C. until HPLC analysis.

Impactor collection stages for all tests were rinsed with DI water andethanol, and air dried prior to each inhaler test trial to avoidcontamination. A new inhaler drug cartridge was used for each of thethree individual tests.

Drug Analysis

All drug content analysis was performed using a Dionex Ultimate 3000nano-HPLC equipped with a Dionex UVD-3000 multi-wavelength UV/VISDetector using a micro flow cell (75 um×10 mm path length, totalanalytical volume 44.2 nl). The column used for the albuterol sulfatewas a Phenomenex Luna (0.3 mm ID×150 mm) C18, 100A (USP L1) column witha column flow rate of 6 μl/min at a nominal pressure of 186 bar. TotalHPLC run time was 6 minutes per sample with approximately 5 minutesflush between each sample. Sample injection was performed with a 1 μlsample loop in full loop injection mode. Detection was with UV at 276 nmfor albuterol sulfate.

HPLC Method and Standards

US Pharmacopeial monograph USP29nf24s_m1218 was followed as a referencemethod for analysis of albuterol sulfate. Briefly, the method involveddilution of an appropriate formulation of albuterol sulfate in mobilephase; 60% buffer and 40% HPLC grade methanol (Acros Organics). Bufferformulation contains reverseosmosis filtered deionized water with 1.13gr of sodium 1-hexanesulfonate (Alfa Aesar) in 1200 ml of water, with 2ml glacial acetic acid (Acros Organics) added. The mobile phase solutionwas mixed and filtered through a 0.45 um filter membrane. The finalmobile phase is a 60:40 dilution of Buffer: MEOH.

Statistical Analysis

Mean and standard deviation were calculated for all triplicate trialsets for each component of: inhaler drug fill, total delivered dose,course particle dose, course particle fraction, respirable particledose, respirable particle fraction, fine particle dose, fine particlefraction, aerosol MMAD and GSD. The number of trials provided for 95%confidence levels for all data sets.

Results

The table below provides a summary of the mass fraction of dropletscollected on each droplet size stage of the Anderson Cascade Impactortesting (Albuterol, 0.5%, Anderson Cascade, 28.3 lpm, 10 actuations). Asshown, over 75% of the droplets of an average diameter of less thanabout 5 μm, and over 70% have an average diameter of less than about 4μm.

Cut Diam. Recovery Mass/Stage Cum. Cum. STAGE NO. μm Mass, ug % % > % <Pre- 10 0.00 0.00 100.00 separator 0 9 94.624 11.05 11.05 88.95 1 5.8109.084 12.73 23.78 76.22 2 4.7 44.263 5.17 28.95 71.05 3 3.3 57.8806.76 35.71 64.29 4 2.1 97.704 11.41 47.11 52.89 5 1.1 272.744 31.8478.95 21.05 6 0.7 107.733 12.58 91.53 8.47 7 0.4 41.530 4.85 96.38 3.62FILTER 31.021 3.62 100.00 0.00 Sum 856.58 ug

The table below provides an alternative format of the summary of Cascadeimpactor testing results, providing the results based on likely area ofdroplet impact in the mouthpiece/throat/coarse, respirable droplets, andfine droplets (Albuterol, 0.5%, Anderson Cascade, 28.3 lpm, 10actuations).

Mouthpiece Losses = 109.4 mcg Cascade Throat Losses = 40.8 mcg TotalCascade Recovery = 897.4 mcg Mouthpiece Losses 12.2% Cascade ThroatLosses  4.6% Coarse Particles (>4.7 um) = 203.7 mcg Coarse ParticulesFraction (>4.7 um) = 22.7% Respirable Dose (0.4-4.7 um) = 621.9 mcgRespirable Fraction (0.4-4.7 um) = 69.3% Fine Particles (<0.4 um) = 31.0mcg Fine Particule Fraction (<0.4 um) =  3.5% Respiratory Delivery Rate(0.4-4.7 um) = 62.2 mcg/Actuation MMAD = 1.93 um Geometric StdDev (GSD)= 1.96 um Mean +/− SD, N = 30   Mouthpiece Throat Coarse Respirable Fine12.2 4.6 22.7 69.3 3.5

FIGS. 21A-21D illustrate the same data in various compilations. FIG. 21Aillustrates percentages of droplets deposited in the mouthpiece, throat,coarse, respirable, and fine. FIG. 21B illustrates the MMAD and GSD forall trial runs, and the average (3 cartridges 10 actuations percartridge; Albuterol, 0.5%, 28.3 lpm; 30 actuations total). FIGS. 21C-1and 21C-2 illustrate cumulative plots of the aerodynamic sizedistribution of the data from FIG. 21B. FIG. 21D illustrates throat,coarse, respirable and fine particle fraction in each trial run, and theaverage (3 cartridges 10 actuations per cartridge; Albuterol, 0.5%, 28.3lpm; 30 actuations total).

Example C: Comparative Droplet Generation Versus Combivent® Respimat®and Proair® HFA

An in vitro study was conducted to evaluate and compare the dropletdelivery device of the present disclosure with two predicated devices,the Combivent® Respimat® inhaler (Boehringer Ingelheim PharmaceuticalsInc., Ridgefield Conn.) and the PROAIR® HFA (Teva Respiratory, LLCFrazer, Pa.). Initially, with reference to FIGS. 22A-22B, a comparisonof the aerosol plumes generated from the droplet delivery device of thedisclosure (the test device) and Respimat Softmist® Inhaler isillustrated. In FIG. 22A, the aerosol plume produced by the test devicehas two distinct flow patterns that are associated laminar flow (1)turbulent flow (2). As previously stated herein, turbulent flow and theformation of eddy currents are produced when droplets have MMADdiameters less than 5 um and lead to the generation of entrained air.Contrasted to this, in FIG. 22B, the plume formed by the RespimatSoftmist® Inhaler displays an aerosol plume is characteristic ofdroplets with high velocities and a wide range of droplet sizes having ahigh momentum and kinetic energy.

The devices were tested dosing Albuterol sulfate aerosol sizedistribution and mass delivery characteristics. As described herein, thedroplet delivery device of the disclosure is a breath-actuatedpiezoelectric actuated device with removable and replaceable reservoir.In this example, the reservoir is designed to contain a therapeuticinhalation drug volume to provide 100-200 breath actuated doses per use.The predicate device Combivent Respimat is a propellant free, pistonactuated, multidose metered inhaler, while the ProAlr HFA device is aCFC free, propellant based metered dose inhale.

A single test device body, and three (3) reservoir/ejector mechanismmodules were tested. All predicate devices were tested in triplicate,for a total nine (9) Cascade Impactor trials. The devices of thedisclosure were tested in triplicate with a new drug reservoir chargedwith 750 μl of 0.5% Albuterol sulfate for each of the three (3) tests.

Particle size distributions were measured using the Anderson CascadeImpactor (ACI) sampling at a constant 28.3 lpm during each test. TheAnderson Cascade Impactor test is as described above in Example B, andcan be used to determine the coarse particle mass, coarse particlefraction, respirable particle mass, respirable particle fraction, fineparticle mass, and fine particle fraction of test aerosols. ACI data canalso be used to calculate the Mass Median Aerodynamic Diameter (MMAD)and Geometric Standard Deviation (GSD) of the aerosol size distribution.Droplet classifications are defined as following: Coarse particlefraction, >4.7 um; Respirable particle fraction, 0.4-4.7 um; Fineparticle fraction, <0.4 um.

The predicate Combivent® Respimat® inhaler was tested using Combivent®Respimat® cartridges containing 20 mcg ipratropium bromide and 100 mcgalbuterol equivalent to 120 mcg dose of albuterol sulfate delivery peractuation. The predicate PROAIR® HFA inhaler was evaluated withcartridges containing 108 mcg albuterol sulfate equivalent to 90 mcgdelivered dose per actuation, while the droplet delivery device of thedisclosure was evaluated using albuterol sulfate at a concentration of5000 ug/ml equivalent to 0.5% albuterol and 85 mcg delivered dose peractuation.

Results from cascade impactor test trials for each inhaler tested intriplicate for Albuterol sulfate are as follows (FIGS. 23A-23B):

Average MMAD for: Test Device, 1.93±0.11, Combivent® Respimat®,1.75±0.19, and PROAIR® HFA 2.65±0.05 μm for dispensing Albuterolsulfate.

Average GSD, for: Test Device: 1.96±0.16, Combivent® Respimat®,2.79±0.25, and PROAIR® HFA, 1.48±0.02.

A summary and comparison of Cascade Impactor Testing of the test device,Combivent Respimat® and Proair® HFA inhalers is shown in in the tablesbelow and in FIGS. 23A-23B. These data show the test device provides thehighest respirable particle fraction for devices tested, (FIG. 23B) witha mean±standard deviation:

For the Test device, 68.7%±3.2%,

Combivent® Respimat®, 57.3%±10.5, and

PROAIR® HFA, 65.2%±2.4%.

Features Drug Test Device Respimat ProAir Number of Actuations Albuterol1 1 1 Actual Drug Concentration Albuterol 85.0 120.0 108.0 (μg/act)Mouth (μg/act) Albuterol 24.3 +/− 12.6 22.6 +/− 1.9 16.1 +/− 4.3  TotalCascade Recovery Albuterol 81.9 +/− 10.3 109.3 +/− 15   121.9 +/− 7.0 (μg/act) Cascade Throat (μg/act) Albuterol 4.0 +/− 0.8  12.1 +/− 11.931.8 +/− 5.0  Throat Fraction (%) Albuterol 4.8% +/− 0.5% 10.2% +/− 9.2% 26% +/− 2.9% Coarse Particle Dose Albuterol 19.0 +/− 4.2  23.9 +/− 1.94.5 +/− 1.0 (μg/act) >4.7μ Coarse Particle Frac (%) Albuterol  23% +/−2.9% 22.1% +/− 2.8% 3.6% +/− 0.7% >4.7μ

Features Drug Pneuma Inhaler Respimat ProAir Respirable Particle DoseAlbuterol 56.2 +/− 6   61.7 +/− 5.5  79.4 +/− 2.7  (μg/act) (0.4-4.7 μm)Respirable Particle Frac Albuterol 68.7% +/− 3.2%  57.3% +/− 10.5% 65.2%+/− 2.4%  (%) (0.4-4.7 μm) Fine Particle Dose (μg/act) Albuterol 2.8 +/−0.3 11.7 +/− 6.1  6.3 +/− 0.9 (<0.4 μm) Fine Particle Frac (%) Albuterol3.4% +/− 0.2% 10.3% +/− 4.1%  5.2% +/− 0.9% (<0.4 μm) MMAD (μm)Albuterol 1.93 +/− 0.11 1.75 +/− 0.19 2.65 +/− 0.05 GSD (μm) Albuterol1.96 +/− 0.16 2.79 +/− 0.25 1.48 +/− 0.02 Confidence level of testingThe test and number of samples tested provide 95% confidence level. 3cartridges/devices each 10 actuations. Total N = 30 actuations

Total Spray Mass Total Spray Mass PNEUMA Ejected from RESPIMAT Ejectedfrom INHALER Cartridge (ml/min) SPERIVA Cartridge (ml/min) DEVICE #3 -0.46 1 0.54 B2D4; CARTRIDGE - B3C1 DEVICE #2 - 0.46 2 0.54 B2D3;CARTRIDGE - B3C5 DEVICE # 1- 0.5 3 0.49 B2D2; CARTRIDGE - B3C3 Avg. 0.47Avg. 0.52 StDev 0.02 StDev 0.03

Example D: Clinical Study—Albuterol Sulfate and Ipratropium Bromide

Using an exemplary ejector device of the disclosure (test device), across over clinical trial was conducted comparing the acutebronchodilatory effects of the test device using albuterol sulfate andipratropium bromide versus no treatment in a group of patients withchronic obstructive pulmonary disease.

Up to 75 patients with COPD will be enrolled. To be eligible for thestudy, subjects at visit 1 must: 1) be previously diagnosed with COPD;2) have at least a 10 pack year smoking history; 3) be prescribed one ormore inhaled bronchodilators; 4) exhibit post bronchodilator FEV1≧25%and <70% predicted normal value using appropriate reference equations.

The study is a crossover, single center, 1 day lung function study tomeasure the acute bronchodilation effect of standard dose albuterolsulfate and ipratropium bromide using an test device of the disclosurein a group of COPD patients.

Subjects may undergo up to a 1 week screening period. If the patient isnot using long acting beta agonists or long acting muscarinicantagonists and has not used a short acting bronchodilator in theprevious 6 hours, no washout period is necessary and can immediatelyproceed with visit 2. If the subject is using a long acting beta agonistthey will be washed out for 48 hours. If the subject is using a longacting muscarinic antagonist the washout period will be one week. Duringthe washout period subjects will be allowed to continue to use inhaledcorticosteroids (ICS), short acting beta agonists (SABA), short actingmuscarinic antagonists (SAMA), leukotriene inhibitors, andphosphodiesterase 4 inhibitors. Subjects experiencing COPD exacerbationsduring the washout period will be excluded from the trial. Subjects whosuccessfully complete the screening period will be included in thetrial.

As described herein, the test devices include piezoelectric actuatedejector mechanisms integrated with reservoir. The reservoir mounts to adevice housing. The device housing has 2 areas 1) a mouthpiece tube and2) a handle. The patient breathes in through the mouthpiece tube toactivate the ejector mechanism. The mouthpiece tube detaches from thehousing and can be sterilized and reused or disposed of after patientuse.

The primary efficacy endpoints will include change in FEV1 during 2 timeperiods: the 20 minutes before receiving a dose of albuterol sulfate andipratropium bromide using the ejector device of the disclosure, and the20 minutes after receiving a dose of albuterol sulfate and ipratropiumbromide from the ejector device of the disclosure. Safety endpoint willinclude vital signs and changes in FEV1. The statistical analysis willinclude an analysis of the change in FEV1 using T-tests.

Interim results demonstrate the use of the ejector device of thedisclosure provides a significant bronchodilatory effect versus notreatment. For instance, with partial enrolment, the following averageFEV1 readings were obtained:

Timepoint FEV1 (Liters)* Baseline 1 1.3733 Baseline 2 (+20 minutes)1.4133 Treatment 1 (+20 minutes after treatment) 1.6688 Treatment 2 (+60minutes after treatment) 1.6844 Treatment 3 (+120 minutes aftertreatment) 1.6522 *Mean baseline FEV1 for the group is 1.29 liters. Meanchange in 20 min FEV1 is 220 cc with a p = 0.000012. Mean change in 60min FEV1 is 260 cc with p < 0.00001. That is a 17% improvement at 20minutes and a 20% improvement at 60 minutes.

As shown in the table above, treatment with the ejector device of thedisclosure improved FEV1 by an average of about 260-275 cc. Thisimprovement is 1.2 to 2 times the increase in broncodilatory effecttypically observed using standard manual inhalers with the same dose ofactive drug.

Example E: Clinical Study—Albuterol Sulfate

Using an exemplary droplet delivery device of the disclosure (testdevice), a cross over clinical trial was conducted comparing the acutebronchodilatory effects of the test device using albuterol sulfateversus the ProAir® HFA Inhaler in a group of patients with chronicobstructive pulmonary disease (COPD).

Up to 75 patients with COPD will be enrolled. To be eligible for thestudy, subjects at visit 1 must: 1) be previously diagnosed with COPD;2) have at least a 10 pack year smoking history; 3) be prescribed one ormore inhaled bronchodilators; 4) exhibit FEV1<70% or at least 10% lowerthan the predicted normal value using appropriate reference equations.

This is a crossover, single center, 2 to 3 day lung function study tomeasure the acute bronchodilation effect of standard dose albuterolsulfate using the test device in a group of COPD patients and to comparethis to the same drug given with a predicate device, the ProAir HFAInhaler, but at half the dose administered with the predicate device.

Subjects may undergo up to a 1 week screening period. If the patient isnot using long acting beta agonists or long acting muscarinicantagonists and has not used a short acting bronchodilator in theprevious 6 hours, no washout period is necessary and can immediatelyproceed with visit 2. If the subject is using a long acting betaagonist, they will be washed out for 48 hours. If the subject is using along acting muscarinic antagonist, the washout period will be up to oneweek. During the washout period subjects will be allowed to continue touse inhaled corticosteroids (ICS), short acting beta agonists (SABA),short acting muscarinic antagonists (SAMA), leukotriene inhibitors, andphosphodiesterase 4 inhibitors. Subjects experiencing COPD exacerbationsduring the washout period will be excluded from the trial. Subjects whosuccessfully complete the screening period will be included in thetrial.

As described herein, the test devices include piezoelectric actuatedejector mechanisms integrated with reservoir. The reservoir mounts to adevice housing. The device housing has 2 areas 1) a mouthpiece tube and2) a handle. The patient breathes in through the mouthpiece tube toactivate the ejector mechanism. The mouthpiece tube detaches from thehousing and can be sterilized and reused or disposed of after patientuse.

The primary efficacy endpoints will include change in FEV1 during 2 timeperiods: the 20 minutes before receiving a dose of albuterol sulfate andthe 20 minutes after receiving a dose of albuterol sulfate using thetest device of the disclosure. Safety endpoint will include vital signsand changes in FEV1. The statistical analysis will include an analysisof the change in FEV1 using T-tests.

Results demonstrate the use of the test device of the disclosureprovides a significant bronchodilatory effect versus no treatment, and asimilar but slightly improved bronchodilatory effect versus treatmentwith twice the dose using a predicate device, the ProAir HFA device.More particularly, there was a statistically significant improvement inFEV1 (120 ml) with the device at a 100 microgram dose of albuterolcompared to no treatment. Further, it was unexpectedly found that theaverage improvement was 11.9 ml greater than the improvement seen withtwice the dose of 200 micrograms using the predicate device, the ProAirHFA inhaler. In this regard, the test device of the disclosure was ableto achieve a similar but slightly improved clinical efficacy at half thedose of the predicate device. The test device was able to deliveryconcentrated doses of a COPD medication and provide meaningfultherapeutic efficacy, as compared to standard treatment options.

The below tables provide detailed data:

Test Device ProAir HFA Baseline Pre 20 min Difference Baseline Pre 20min Difference 0.54 0.49 −0.05 0.65 0.64 −0.01 1.3 1.33 0.03 1.14 1.210.07 0.92 1 0.08 1.09 1.02 −0.07 1.26 1.32 0.06 1.18 1.3 0.12 1.59 1.640.05 1.33 1.39 0.06 0.63 0.68 0.05 0.76 0.74 −0.02 0.68 0.84 0.16 0.80.76 −0.04 1.09 1.01 −0.08 1.28 1.23 −0.05 0.85 0.85 0 1.13 1.13 0 1.221.16 −0.06 1.08 1.07 −0.01 1.28 1.24 −0.04 2.14 2.11 −0.03 2.15 2.13−0.02 1.18 1.16 −0.02 0.98 1.04 0.06 1.36 1.46 0.1 1.35 1.43 0.08 0.890.95 0.06 1.05 1.24 0.19 1.46 1.48 0.02 1.41 1.53 0.12 0.97 1 0.03 0.530.41 −0.12 0.86 1.03 0.17 0.68 0.63 −0.05 0.63 0.65 0.02 1.45 1.77 0.321.67 1.7 0.03 2.04 2.15 0.11 1.08 1.07 −0.01 0.97 1 0.03 1.9 1.95 0.05mean change 0.04381 mean change 0.022381

Test Device ProAir HFA Pre 20 min 20 Post Difference Pre 20 min 20 PostDifference 0.49 0.76 0.27 0.64 0.82 0.18 1.33 1.33 0 1.21 1.23 0.02 11.03 0.03 1.02 1 −0.02 1.32 1.41 0.09 1.3 1.43 0.13 1.64 1.8 0.16 1.391.77 0.38 0.68 0.82 0.14 0.74 0.86 0.12 0.84 0.92 0.08 0.76 0.91 0.151.01 1.09 0.08 1.23 1.29 0.06 0.85 1.05 0.2 1.13 1.15 0.02 1.16 1.36 0.21.07 1.13 0.06 1.24 1.33 0.09 2.11 2.42 0.31 2.13 2.31 0.18 1.16 1.470.31 1.04 1.02 −0.02 1.46 1.56 0.1 1.43 1.46 0.03 0.95 1.17 0.22 1.241.39 0.15 1.48 1.66 0.18 1.53 1.41 −0.12 1 0.92 −0.08 0.41 1.17 0.761.03 0.52 −0.51 0.63 0.67 0.04 0.65 0.72 0.07 1.77 1.79 0.02 1.7 1.940.24 2.15 2.25 0.1 1.07 1.09 0.02 1 1.05 0.05 1.95 2.27 0.32 mean change0.20476 mean change 0.108571

Example F: Delivery of Large Molecules—Local and Systemic Delivery

Using an exemplary droplet delivery device of the disclosure, testing isconducted to verify that large molecules including epidermal growthfactor receptor (EGFR) monoclonocal antibody, bevnizumab (Avastin),adalimumab (Humira) and etanercept (Enbrel) is not denatured or degradedby ejection through the device of the disclosure, and to verify thatlocal pulmonary delivery and/or systemic delivery of the active agent isachieved.

Droplet Characterization:

To verify droplet generation, droplet impactor studies may be performed,as described herein.

Gel Electrophoresis:

To determine the stability of active agent after droplet generation, thegenerated stream of droplets including the active agent is collected andthe molecular weight of the active agent is verified using gelelectrophoresis. Gel electrophoresis will show that there is negligiblechange in the electrophoretic mobility, and hence the molecular weight,of the post-aerosol active agent from that of the control, i.e., wholeEGFR antibodies, bevacizumab, adalimumab, or etanercept. The gel willalso show that is no evidence of smaller fragments of the protein on thegel, further confirming that the aerosol generation will not cause anyappreciable protein degradation. In addition, the gel will show noapparent aggregation of the antibody or protein, which is significant asmany inhalation devices have been reported to be prone to proteinaggregation and hence unsuitable for the pulmonary delivery of largemacromolecules such as proteins and antibodies.

Size Exclusion Chromatography (SEC):

Alternately, to determine the stability of active agent after dropletgeneration, the generated stream of droplets including the active agentmay be collected and SEC-HPLIC may be employed to monitor for anychanges in large molecule aggregation and protein fragment content.Soluble protein aggregates and protein fragment content may becalculated by comparing respective peak area under the SEC-HPLC curve ofdispensed protein solutions with controls (solutions remaining in thedevice reservoir).

Drug solutions for testing include Enbrel, (ENBREL® single-use prefilledsyringes in 25 mg (0.51 mL of a 50 mg/mL solution of etanercept), andinsulin, (Humalog, 200 units/ml, 3 ml kwikpens)

ENBREL® (etanercept) is a dimeric fusion protein consisting of theextracellular ligand-binding portion of the human 75 kilodalton (p75)tumor necrosis factor receptor (TNFR) linked to the Fc portion of humanIgG1. The Fc component of etanercept contains the CH2 domain, the CH3domain and hinge region, but not the CH1 domain of IgG1. Etanercept isproduced by recombinant DNA technology in a Chinese hamster ovary (CHO)mammalian cell expression system. It consists of 934 amino acids and hasan apparent molecular weight of approximately 150 kilodaltons.

SEC is performed with a Yarra™ 3 um SEC-2000 LC column 300×7.8 mm,SecurityGuard cartridge kit and SecurityGuard cartridges GFC-2000, 4×3mm ID. Fifty microliters of Enbrel from the syringe (ENBREL® single-useprefilled syringes in 25 mg/0.51 mL of a 50 mg/mL solution ofetanercept) is diluted (4:1) (4 parts, 200 mcl of the mobile phasebuffer solution to 1 part, 50 mcl Enbrel from syringe). Fifty microliterof the diluted Enbrel is injected and separation was performed at a flowrate of 1.0 ml/min. The mobile phase buffer system included a PHOS.BUFF. SALINE. (PBS) solution and 0.025% NaN₃, pH 6.8. UV detection isperformed at 280 nm.

To calculate and compare effects of droplet generation through anejector mechanism of the disclosure, the total area under the curve ofthe UV signal at 280 nm versus elution time for controls is comparedwith the aerosolized samples, which is set to 100%.

Fifty microliters (mcl) of insulin, (Humalog, 200 units/ml, 3 mlKwikpens) is directly drawn from the Kwikpen and injected into the SECcolumn for analysis while 200 mcl of the Kwikpen solution is directlyinjected into the ampule/cartridge before actuation and aerosolgeneration with the test device. Aerosol collection and SEC is performedin a similar fashion as for the Enbrel analysis and aerosol collection.

An ampule/cartridge is filled with either 0.20 ml of Enbrel® (50 mg/ml)diluted 4:1 (10 mg/ml)(4 parts (200 mcl) of PBS and 0.025% NaN₃ and 1part (50 mcl of Enbrel solution from the syringe). After 20 actuationsand aerosolization, about 150 mcl of the aerosolized Enbrel solution isrecovered and collected in the polypropylene tube located below theejector mechanism. The control consists of the diluted Enbrel solution,50 mcl of which is injected into the SEC column for analysis.

Insulin solutions from a Humalog, 200 units/ml, 3 ml Kwikpen is drawnwith a syringe and 200 mcl is injected directly into thereservoir/ejector mechanism module and mounted onto a test device beforeactuation. Aerosol emerging from the test device is collected by placinga 0.5 ml polypropylene test tube directly below the aperture plate.Twenty actuations aerisolization resulted in the recovery of about 150mcl of the aerosol insulin spray. Fifty microliters of the collectedaerosol spray is injected onto the SEC column for analysis, while 50 mclof the Kwikpen insulin solution is injected onto the SEC column forcontrol samples.

Results; Enbrel

Referring to FIG. 24A-24B, are SEC chromatographs of Enbrel® diluted4:1, (10 mg/ml) control (FIG. 24A) and aerosolized Enbrel solutions(FIG. 24B) collected from the test device after actuation. A single mainpeak is evident in chromatographs of the aerosolized Enbrel solutionwith an elution time of about 25 minutes. The tables below compare areasunder the UV curves for the various peaks emerging at specified elutiontimes (min) for controls and aerosolized Enbrel solutions.

Enbrel Stability Studies: Aerosol Generation using Test Device Peak Area% Peak 1 Peak 2 Peak 3 Peak 4 Peak 5 (Ret (Ret (Ret (Ret (Ret Time)Time) Time) Time) Time) control 1 2.428 96.676 0.373 0 0 (4.336) (4.827)(11.628) control 2 3.041 95.909 0.351 0 0 (5.326) (5.785) (12.605)Aerosolized 2.796 90.789 0.424 0.357 5.130 S1 (5.372) (5.853) (12.675)(13.051) (25.139) Aerosolized 3.476 92.112 0.361 0.352 3.428 S1 (5.338)(5.821 (12.625) (13.020 (25.082

Peak 4 Peak 5 Aerosolized 0.357 5.123 S1 Aerosolized 0.352 3.428 S2 Avg.0.3545 4.2755 Std. Dev. 0.0035 1.1985

These data demonstrate that the test device can deliver 95.4% of Enbrelthat is structurally unchanged after delivering an aerosol dose, whileonly 4.6% of the dose leads to formation of molecular fragments withelution times of 13 and 25 minutes.

Gravimetric analysis was performed by weighing the Enbrel solutionfilled ampule before and after dosing. The average of five doses(actuations) were analyzed with an average of 4.25 mg+/−0.15 mg. Thetotal delivered dose of Enbrel per actuation is therefore 42.5 mcg peractuation. In comparison, actuation of distilled water with the sameampule resulted in a delivered dose of 9.26 mg.+/−1.19 mg.

Results; Insulin

Referring to FIGS. 25A-25B, are SEC chromatographs of Insulin fromKwikpen (200 U/ml; 34.7 mcg/U; 6.94 mg/ml) as control (FIG. 25A) andaerosolized from the test device (FIG. 25B). About 150 mcl ofaerosolized Insulin solutions were collected from the test device afteractuation. A single major peak is evident in the chromatograph of theaerosolized Insulin solution with an elution time of about 25 minutes.The tables below compare areas under the UV curves for the various peaksemerging at specified elution times for controls and aerosolized Insulinsolutions. Retention times are in minutes.

Insulin Stubility Studies: Aerosol Generation using Pneuma InhalerDevice Peak Area % Peak 1 (Ret Peak 2 (Ret Peak 3 (Ret Time) Time) Time)control 1 29.926 69.630 0 (10.786) (22.603) Aersolized 28.721 67.8072.797 S1 (10.823) (22.508) (25.017) Aersolized 27.881 69.780 2.184 S2(10.878) (22.726) (25.247)

Peak 3 Aersolized 2.797 S1 Aersolized 2.184 S2 Avg. 2.4905 Std. Dev.0.4335

These data demonstrate that the test device can deliver 97.5% of theejected dose of Insulin that is structurally unchanged while 2.5% of theejected dose forms a fragment which elutes at ˜25 minutes.

Gravimetric analysis was performed by weighing the Insulin solutionfilled ampule before and after dosing. The average of five doses(actuations) were analyzed with an average of 5.01 mg+/−0.53 mg. Thetotal delivered dose of Insulin per actuation is therefore 34.8 mcg peractuation.

Antibody/Protein Binding Assay:

The activity of the aerosolized antibody or protein is demonstrated bytesting its ability to bind to its antigen or target on a cell surface,i.e., EGFR, TNFα, etc. Flow cytometry data of cells incubated witheither aerosolized or non-aerosolized active agent will reflectactivity. Specifically, the data will show a shift in the fluorescenceintensity of the cells incubated with non-aerosolized fluorescentlylabelled active agent compared to that for the untreated cells. Asimilar shift will be obtained with cells incubated with aerosolizedactive agent, suggesting that the post-aerosolized active agent retainsits immunoactivity and hence its ability to bind to its target receptoron the cell surface.

Clinical/In Vivo Testing:

Using an exemplary ejector device of the disclosure, as generally shownin FIGS. 1A-1E, a clinical trial is conducted to assess pharmacokineticdata following administration of large molecule active agents. pK datawill verify that large molecule active agents are successfullysystematically administered.

1. A method for generating and delivering a fluid as an ejected streamof droplets to the pulmonary system of a subject in a respirable range,the method comprising: (a) generating an ejected stream of droplets viaan electronically breath actuated droplet delivery device, wherein atleast about 50% of the ejected stream of droplets have an averageejected droplet diameter of less than about 10 μm; and (b) deliveringthe ejected stream of droplets to the pulmonary system of the subjectsuch that at least about 50% of the mass of the ejected stream ofdroplets is delivered in a respirable range to the pulmonary system of asubject during use.
 2. The method of claim 1, wherein the ejected streamof droplets are subjected to an approximate 90 degree change oftrajectory within the electronically breath actuated droplet deliverydevice such that droplets having a diameter greater than about 5 μm arefiltered from the ejected stream of droplets due to inertial forces,without being carried in entrained airflow through and out of thepiezoelectric actuated droplet delivery device to the pulmonary systemof the subject.
 3. The method of claim 2, wherein the filtering ofdroplets having a diameter greater than about 5 μm increases the mass ofthe ejected stream of droplets delivered to the pulmonary system of thesubject during use.
 4. The method of claim 1, wherein the ejected streamof droplets comprise droplets having an average ejected droplet diameterof between about 5 μm to about 10 μm.
 5. The method of claim 1, whereinthe ejected stream of droplets comprises a therapeutic agent for thetreatment of a pulmonary disease, disorder, or condition.
 6. The methodof claim 1, wherein the electronically breath actuated droplet deliverydevice comprises: a housing; a reservoir disposed within or in fluidcommunication with the housing for receiving a volume of fluid; anejector mechanism in fluid communication with the reservoir configuredto generate an elected stream of droplets; at least one differentialpressure sensor positioned within the housing, the at least onedifferential pressure sensor configured to activate the ejectormechanism upon sensing a pre-determined pressure change within thehousing to thereby generate an ejected stream of droplets.
 7. The methodof claim 9, wherein the aperture plate of the electronically breathactuated droplet delivery device comprises a domed shape.
 8. The methodof claim 9, wherein the electronically breath actuated droplet deliverydevice further comprising a laminar flow element located at the airflowentrance side of the housing and configured to facilitate laminarairflow across the exit side of aperture plate and to provide sufficientairflow to ensure that the ejected stream of droplets flows through thedroplet delivery device during use.
 9. The method of claim 6, whereinthe ejector mechanism comprises a piezoelectric actuator and an apertureplate, the aperture plate having a plurality of openings formed throughits thickness and the piezoelectric actuator operable to oscillate theaperture plate at a frequency to thereby generate an ejected stream ofdroplets.